We’re going to start off talking about the biology of renal cell carcinoma [RCC]. As we know, the most common histology for renal cell carcinoma is clear cell renal carcinoma. We’re going to talk about clear cell carcinoma since that is the most common disease that we see, the biology of which has evolved from our understanding dating back from the 1980s. There is increasing awareness of the complexity of clear cell renal cell carcinoma, which has multiple molecular profiles, each with unique biologic properties.

Sporadic clear cell renal cell carcinoma is associated with the loss of function and alterations of the 

 gene, which is characterized by neoangiogenesis and up-regulation of the hypoxia inducible factor [HIF].Wild-type VHL protein functions as a ubiquitous ligase participating in the upregulation of HIF in patients bearing HIF alterations. The resulting high levels of HIF result in upregulation of vascular endothelial growth factor, which activates VEGFR, which triggers the PI3K/Akt signaling cascade.

Downstream mTOR is activated and leads to the transcription of a variety of tumor promoting factors, resulting in increasing cellular migration and angiogenesis. It has been found that several drivers of tumor progression, including VEGFR and other transmembrane receptors, may potentially drive metastases including AXL and MET. These studies led to a therapeutic development of anti-VEGF and anti-mTOR agents in the treatment of clear cell renal cell carcinoma.

Improved understanding of T-cell biology has defined the role of immune checkpoints []in curbing immune responses to prevent autoimmunity while simultaneously allowing tumor growth escape. This led to the development of immune checkpoint inhibitors designed to remove the brakes of immune activation against tumors.

Renal cell carcinoma is a malignancy that primarily affects individuals aged in their 40s and up. It is more common in men than women. The most well recognized risk factor for renal cell carcinoma is tobacco use. Renal cell carcinoma is comprised of a number of different malignancies. The most common of these is called clear cell carcinoma, which comprises between 70% and 80% of diagnosed kidney tumors. There’s a spectrum of other malignancies that arise from the kidney, and these are generally referred to as non–clear cell renal cell carcinoma, with the most common variance being papillary RCC or chromophobe tumors.

The initial presentation has most often been a hematuria that’s either observed by the patient, reported to the physician, or picked up by routine urinalysis. Other common presenting signs or symptoms are flank pain, or either an abdominal or flank mass. Historically, a triad of hematuria, flank mass, and abdominal pain were considered classic for renal cell carcinoma. However, because of our improvements in medical imaging and screening for various conditions, now the most common way this tumor is noticed is as an incidental finding on a radiograph that’s performed for some other reason.

The classic method of diagnosis has been to do ultrasounds to assess people with signs and symptoms of gall bladder disease, or sonograms or CT scans to investigate trauma or any other signs or symptoms. Nowadays, up to 60% of people who are diagnosed with kidney cancer will be diagnosed based on this so-called incidental finding. As a result of this new pattern of diagnosis, the tumors are often noticed at a lower stage and when they’re smaller, and are more amenable to surgical resection and cure. However, surgery remains the mainstay of therapy for kidney cancer and the only curative therapy. Still, a fair number of patients either present with metastasis, or about 30% will relapse following a nephrectomy, and all those patients will eventually require systemic therapy.

Renal Cell Carcinoma and Novel Therapies

For patients who do have metastasis, the mainstay for kidney cancer has been good supportive care. This can be surgery, if it is needed urgently, or radiation therapy, or other pain medications or support care measures. For the most part, the role of surgery in supportive care has been to remove the kidney primary, a procedure called cytoreductive nephrectomy, particularly if it’s symptomatic with hematuria. Surgery has been utilized in bone metastases that either have pathologic fracture or are at risk for fracture. Radiation therapy applied to treat painful bone metastasis or stereotactic radiation is the primary modality now for brain metastasis.

Those are the supportive care measures that take priority and need to be utilized to manage more urgent adverse events or symptoms from the malignancy in the setting of the overall care of metastasis. There has been tremendous progress in systemic therapy for renal cell carcinoma. The treatments utilized have largely been tyrosine kinase inhibitors [TKIs] or immunotherapies. For the most part, these medications have not been curative. They have been shown to result in responses, improve progression-free survival, and now more recently, produce gains in overall survival. But during that period, it is very important to maintain and to utilize treatments that improve a patient’s quality of life, minimize adverse events from therapy, or improve safety.

Efficacy has been the primary concern of our therapy. First, it was important to find agents with activity, then improve progression-free survival. We are now looking for big gains in overall survival. During that time, improving patients’ quality of life and managing toxicities are primary goals.

Going back to the historical perspective on our available treatments of renal cell carcinoma, we have to go back to the work that predates the approval of all these therapies with the assistance of the Cytokine Working Group and other groups as well. The eventual FDA approval of high-dose IL-2 [interleukin-2] in 1992 was a breakthrough. Using high-dose IL-2, or sometimes using high-dose IL-2 with interferon or low-dose interferon, has led to the initial immunotherapies that we currently use, but using different agents, more toxic agents.

It was 13 years until the approval of sorafenib, and only 5 weeks after that, we get the development of sunitinib and FDA approval. Looking back at the JCO [

] article that Nick Vogelzang [MD, FASCO, FACP] wrote a comment on, we had at that point the embarrassment of riches. We were filled with 3 drugs we could use to treat renal cell carcinoma, and it was really the breakthrough. Through expanded accesses, a lot of physician practices, including my own, have access to these agents.

Going back and looking at the research they did, including clinics, using these 2 agents and even sequencing these 2 agents has led to our concept of recognizing back in 2005 and 2006 what we call now sequencing TKI followed by TKI. Two years after that, we now had mTOR inhibitors temsirolimus and everolimus. Shortly after that, we have the approval of crizotinib followed by axitinib.

Then there is a little downtime, then suddenly we had the new drugs. We had nivolumab in November of 2015. Suddenly, we have immunotherapy rearing its beautiful head 23 years later. Shortly after we had cabozantinib. We had lenvatinib, and now we have gone to a new phase of combination therapies. Looking back, how immunotherapy started us off, toxicities, a lot of patients avoided receiving those therapies. The development of oral TKIs kept patients on active therapies at home; mTOR was in the office with temsirolimus.

Suddenly, we are back to immunotherapy. It’s really now the single agents that we’ve derived benefits from, and over the last few years, the combination of these therapies has given us a lot more benefit to patient care, not just in terms of efficacy, but tolerability as well.

Supportive Care and Systemic Therapy for RCC

For the most part, historically, most patients with RCC [renal cell carcinoma] have presented to the urologist. It has largely been for evaluation of a renal mass. The referral has been from various caregivers, including primary care physicians or gynecologists. Usually the renal mass is identified either in a setting of hematuria or by an imaging study that is done to assess a different condition, and they identify a renal mass. The first responder for kidney cancer, historically, and the person who’s been primarily involved with management, is the urologist. The care has largely been surgical regarding resecting the tumor. 

There are some patients who present with metastasis. About 25% of people with the initial diagnosis of kidney cancer will have stage IV disease, meaning they have distant metastasis. Sometimes these metastases can be asymptomatic, or they can produce symptoms. The symptoms that occur can include pain in the bone area, since this tumor metastasizes frequently to bone. It can present with respiratory symptoms, hemoptysis, or a cough, because of the frequency of lung metastasis. It can present with a mass in the abdomen and enlarged left supraclavicular lymph node. These are common presentations. 

The other thing that has been noteworthy for renal cell carcinoma is the occurrence of paraneoplastic syndromes. Historically, paraneoplastic syndromes have been ascribed to renal cell carcinoma. They include anemia, polycythemia, and hypercalcemia. There’s another paraneoplastic syndrome called Stauffer syndrome, which presents as elevated liver function test abnormalities in the absence of metastasis. 

Of the various different malignancies, renal cell carcinoma has been the one most notably connected with paraneoplastic syndromes and was actually referred to as the internist’s tumor, because of the wide variety of different manifestations of this cancer and its insidious nature and presentation that eventually leads to a diagnosis.

 As medical oncologists, patients often come to us having already been given a diagnosis of renal cell carcinoma or a renal mass. We are suddenly given a sense of ease when talking to patients about a diagnosis they have. But the community oncologists or community primary care physicians may not have that luxury. When we do have patients who come to our clinic and we are having the ability to take care of these patients with a renal mass, the standard work-up has to come into play.

You must get a CBC [complete blood count], a chemistry panel, an LDH [lactate dehydrogenase test], a urinalysis; you want to gauge the amount of bleeding in the urine. Hematuria will be a very important factor. We perform CT scans or MRIs [magnetic resonance imaging tests] of the abdomen and pelvis, chest x-ray, and perhaps a CT scan of the chest, depending on symptoms.

And if clinically indicated, using an elevated alkaline phosphatase [test] with patients having pain, getting patients to have a bone scan, imaging the brain either via a CT scan or an MRI, and performing a CT of the chest, again, depending on suspicion, symptoms, or an abnormal chest x-ray, is recommended.

Ultimately, we need to do a biopsy. If the patient has advanced disease, sometimes you can biopsy the site of the metastases as compared to having to do a kidney biopsy. But it really is important that a work-up be done so you can identify the extent of the patient’s disease status prior to consideration of therapy. If the patient has a central tumor, you want to make sure you are not dealing with a urothelial carcinoma as opposed to a renal cell carcinoma, so a urine cytology. 

Ureteroscopies and biopsies may be important as well to document the patient’s histology prior to concluding that you are dealing with a renal cell carcinoma.

In terms of the genomics that are attributed to renal cell carcinoma, the key genomic finding has been loss of chromosome 3p and mutation of the VHL gene. For clear cell carcinoma, that is really the path of mnemonic mutation that is associated with this tumor. There have been other mutations that have been found in RCC. One is BAP1, another is SETD2, and a third is PBRM1. These are all chromosomes located on 3p. They have been more recently ascribed and are of importance prognostically.

It is possible PBRM1 is associated with a favorable prognosis, and that BAP1 is associated with an adverse prognosis. For the most part, kidney cancer is one of the few malignancies where we really have not been able to identify targetable mutations in the genomic structure. The one that is targeted is the VHL mutation. Essentially, all patients with clear cell carcinoma either have a mutation of this gene or else some sort of silence by a different process like methylation.

Genomics are important in diagnosis in terms of looking for VHL mutation and chromosome 3p abnormalities. But they really have not been able to, aside from the use of VEGFR inhibitors, been able to direct our therapy. In medical management, we recommend that, across the board for malignancies, genomic profiling be performed. 

Regarding RCC, there is some prognostic information that can be derived from the genomic mutations. But aside from that, it is really a work in progress. We are looking to see if we can identify better signals for our therapy based on the genomic abnormalities of the patient.

When we see these patients come into the office and we have done the work-up, we feel as if we have enough information, then we may have a plan to take care of these patients. Initially, dating back 25 years, we believed that cytoreductive nephrectomy was the initial treatment plan for patients, even in the setting of metastases.

With the newer publications about evaluating patients receiving oral TKI [tyrosine kinase inhibitor] therapy, we were having patients undergo cytoreductive nephrectomies, and that has proven that sometimes cytoreductive nephrectomies do not have to be considered. There are times where the patients’ challenges make us think that our course of initial management must be adjusted. Patients having hematuria may be subtle, but if a patient begins to have symptomatic hematuria, though we may have thought that an oral tyrosine kinase inhibitor as initial therapy may be beneficial, surgery may have to be considered to allow these patients the ability to control their symptoms. Patients with bone metastases can have extensive diseases where palliative radiation therapy may be beneficial. 

Pain may be associated with a metastases or the primary tumor itself, which should be addressed and which may expedite our treatment plan, when we compare surgery vs initial or systemic therapy. Hypercalcemia be a complication of renal cell carcinoma [RCC]. The extent of the disease that patients have, whether they have a tumor thrombus, which may cause vascular compromise, may also change our initial thought processes from systemic therapy to surgical intervention.

This must be utilized through a multidisciplinary team: vascular surgeons, nephrologists, and urologists can offer a significant help in assisting with patient care. The challenge that we feel the most is something that we see on the first visit: the patient’s functional performance status.

At times, the patients can feel relatively asymptomatic or minimally symptomatic, in which case proceeding with therapies may be no challenge. But if a patient’s functional performance status is decreased because of a tumor or other comorbid conditions, our therapies may have to be adjusted, or the considerations of surgeon may have to be altered simply because of the patient, not just the cancer.

 The NCCN [National Comprehensive Cancer Network] has developed guidelines for systemic therapy for kidney cancer. These are widely followed. For the most part, patients are grouped into first-line therapy and subsequent therapy, and by the clear cell histology and the non–clear cell histology, through the NCCN guidelines.

Most of the evidence, time, and effort have gone into the clear cell population in first-line therapy because that is where most of the data are. For the NCCN guidelines, for patients who have clear cell RCC, some of the regimens that are used that are considered level 1 are pembrolizumab plus axitinib, which is preferred, or sunitinib and pazopanib for a patient with favorable risk. This also receives a high ranking. Other regimens are included in treatment recommendations for patients with favorable risk, including ipilimumab and nivolumab, as well as axitinib and nivolumab. 

In the patients who have intermediate or poor risk, in first-line therapy for clear cell renal cell carcinoma, the 2 top regimens recommended by the NCCN are either the nivolumab plus ipilimumab regimen, or else axitinib plus pembrolizumab. There are other options for other patients as well, including cabozantinib, or axitinib plus avelumab, but the nivolumab plus ipilimumab regimen or axitinib plus pembrolizumab are really the 2 most strongly recommended. In subsequent therapy, the evidence for therapy has been based on patients treated with TKIs in first-line therapy. There is very little evidence or studies that have addressed the best way to treat a patient who has progressed on an IO [immune oncology] combination. 

Most of the recommendations per NCCN include nivolumab, lenvatinib plus everolimus in second-line therapy for patients who have had TKI, and cabozantinib. These recommendations are largely based on patients who have progressed on sunitinib or pazopanib. That has changed with these new combinations. It has illuminated an unmet need to define best treatment in that setting. There are much fewer data about what therapy is effective in patients who have non–clear renal cell carcinoma. There are a number of different agents that have been developed for clear cell renal cell carcinoma that have been extrapolated to treat non–clear cell renal cell carcinoma. They do have some level of effectiveness, and so they are included in recommendations. 

The treatment that has been most extensively studied is sunitinib. Recently, there has been enthusiasm in studies around cabozantinib in that setting. Most recently, there was a paper outlining the efficacy for lenvatinib plus everolimus to treat non–clear cell renal cell carcinoma. Those are 3 big contenders for that population.

Newly Diagnosed RCC: Treatment Planning

When a patient presents to the office and you are given the luxury of having some laboratory analysis, you should already try to risk-categorize your patients. Think about how we have done it in the past, going by a gut feeling, or whether we think the patient can tolerate it. But many of these risk categorizations are important to not only define the patients’ risk but also our treatments.

Dating back to the initial immunotherapy clinical trials, the MSKCC [Memorial Sloan–Kettering Cancer Center] risk categorization first presented by Robert Motzer, [MD,] utilizes parameters including patient’s functional performance status, time from initial diagnosis to first therapy, and other parameters including hemoglobin, LDH [lactate dehydrogenase], as well as calcium level. When the patients come to your office, you already have seen the patient’s functional performance status.

You already know the time of diagnosis to when you first see the patient in therapy, and you have a CBC [complete blood count]. Automatically, you have 3 of the 5 parameters to define the patients’ risk. Favorable risk patients are those who have no risk factors. I define risk factors as elevated calcium levels, hemoglobin that’s less than 12 [g/dL], and LDH greater than the upper limit of normal. If you have 1 to 2 risk factors, you are at intermediate risk, and if you have 3 or more, then you are at a high risk.

More recently, Daniel Heng [MD, MPH] has formed the International Metastatic Renal Cell Carcinoma Database Consortium criteria, or the IMDC, which utilizes most of those same factors. It utilizes the patients’ functional performance status, time from diagnosis to initial therapy, hemoglobin level, as well as calcium level. But they removed the LDH, and they are now utilizing the number of white blood cells and platelets as a measurement. They consider both an elevated white blood cell count and an elevated platelet count. Usually, those conditions are signs of inflammatory processes, most likely due to the tumor.

Under their categorization, if you have no risk factors, you’re considered to be of favorable risk. If you have 1 to 2 risk factors, then you are of intermediate risk. If you have 3 or more risk factors, you are considered to be at poor risk. This is important because the new NCCN [National Comprehensive Cancer Network] guidelines have incorporated the risk categorization of patients and have determined whether their therapies may be beneficial to these patients. 

After analyzing the data to define the risk categorization and looking at more recent clinical trials like CheckMate 214 and the KEYNOTE-426, we have been given more insight into and recommendations on how to treat these patients. It is a simple task, since there is a nominal amount of effort, but it is quite important for patient care.

Risk models have been described for advanced RCC [renal cell carcinoma], primarily in first-line treatment, and are important tools for the clinician. They aid the clinician in assessing prognosis, assessing outcome to clinical trial, and now, directing treatment. The first model was a model that I developed with my colleagues at Memorial Sloan Kettering, called the MSKCC model. It was developed in the cytokine era. Most of the patients had treatment with interferon, interleukin-2, or clinical trials with those drugs. We developed that because people were making comparisons between outcomes at various centers with interferon or interleukin- 2, and they were noticing that this trial is reporting much better results than a trial done at a different center. 

There really was no language that could be used to assess the relative prognosis in that group. That was one of the driving factors behind the creation of the MSKCC model. The other was to utilize it for stratification factors in phase 3 trials. We initially developed the MSKCC risk group. It was based on 5 preclinical factors that all predicted a short survival. They included anemia, high calcium, low performance status, and a high lactate dehydrogenase level. We also considered prior nephrectomy at first, but that was changed to diagnosis from treatment to start of therapy of less than a year. 

That was the first system that we were able to categorize patients by 0, 1, 2, or 3 or more risk factors into favorable, intermediate, and poor risk groups. That was revisited in the targeted therapy era by Dr Heng and Toni Choueiri, [MD]. They developed the international criteria that we use. It was a modification of the MSKCC, whereby the lactate dehydrogenase came out of the model, and instead they consider high platelet and neutrophil counts. That fits patients in the targeted therapy era much better, and that system has been used in studies to evaluate the new IO [immune oncology] combinations. It has proved predictive in that setting. Based on those criteria, there has been some differential outcomes for IO therapy versus TKI [tyrosine kinase inhibitor] therapy, which is now used to direct and drive treatment.

Risk Stratification in Renal Cell Carcinoma

Utilizing the risk categorization has now led to the NCCN [National Comprehensive Cancer Network] offering approaches toward systemic therapy for patients with relapsed or stage IV renal cell carcinoma [RCC]. In the category of favorable risk, this is all data-driven, there has been previous approval for the usage of sunitinib or pazopanib single-agent oral tyrosine kinase inhibitor [TKI] therapy. 

Based upon the KEYNOTE-426 clinical trial, the indication of using axitinib and pembrolizumab [Keytruda] or what we call axi-pembro, has gotten approval in the population of patients who are considered to be at favorable risk. In patients who are poor or intermediate risk, we utilize regimens of ipilimumab [Yervoy] and nivolumab [Opdivo], or ipi-nivo, again, axitinib and pembrolizumab. Based upon the CABOSUN clinical trial, cabozantinib has been approved and is a first-line regimen in patients with intimate or poor risk.

There are other regimens one can utilize in favorable risk, poor risk, and intermediate risk patient populations, many of which are based upon clinical trials. There has been an accumulation of data over the last 5 years, but going back to the simplicity of having a patient’s risk categorized during their initial visit or after you get the laboratory results makes it easy for us to think about what regimens we should be considering based upon the clinical trials that we were talking about.

The risk factors used in the IMDC [International Metastatic RCC Database Consortium] criteria are a short time from diagnosis to start of systemic therapy of less than a year, high calcium, low performance status, KPS 70 [Karnofsky Performance Status score of 70], anemia, elevated white blood cell count, or an elevated platelet count. If patients have none of those risk factors, those are categorized as patients at favorable risk. If they have 1 or 2, they are of intermediate risk. If they have 3 or more, the patient falls into the poor risk category. For the most part, people with favorable risk, their tumors have small volume disease. They will often relapse a year or so after treatment or have very slow progression of minute nodules in their lungs. They can be asymptomatic, and their condition really doesn’t affect their organ function. In those patients, the tyrosine kinase inhibitors appear to be very effective.

The standard of care has been sunitinib or pazopanib in that population. Most patients live for years in that situation. As a matter of fact, many of those patients do not need systemic therapy immediately. The first management strategy upon discovery of metastasis is often just to monitor the patient, not to treat them with active systemic therapy, which has its toxicities. Then we follow patients along with CT scans. With many of those patients, we can delay systemic therapy for years, or avoid it entirely. The patients with favorable risk are generally the people who have low volume disease and are feeling well. For those in that population, the big studies of IO [immune oncology] combinations showed a benefit in response rate for axitinib plus pembrolizumab and also axitinib plus avelumab in that favorable risk group. They have higher response rates and longer progression-free survival, but a similar survival rate. 

With ipilimumab, nivolumab, the favorable risk group actually had higher response rate and longer progression-free survival with the sunitinib TKI than they did with the ipilimumab, nivolumab. The thought had been that those patients are probably best managed with either TKI monotherapy or TKI plus pembrolizumab or avelumab. There is a case, however, for giving favorable risk patients ipilimumab, nivolumab. For the most part, those patients, because they live a long time, have a slowly progressive disease. They can receive multiple lines of therapy. The tyrosine kinase inhibitors that we use often develop chronic toxicities, which are more problematic over time and which can impair quality of life. With ipilimumab, nivolumab, although the response rate is lower, in general, the quality of life is better overall for the patients, especially when the patient is past the induction period with ipilimumab plus nivolumab.

The responses can be very durable. There is a higher rate of complete responses. There is some controversy in terms of what is the optimal way to treat those patients. There is certainly a school of thought that recommends ipilimumab, nivolumab, at least as initial treatment, to see if we could obtain a durable response and good quality of life for those patients. In the intermediate and poor risk patients, the data are different. In the trials of IO combinations with either ipilimumab plus nivolumab or axitinib plus pembrolizumab, or axitinib plus avelumab, there were higher response rates when the IO treatment was included, with longer progression-free survival rates. For ipilimumab plus nivolumab and axitinib plus pembrolizumab, there was a benefit and overall survival compared to sunitinib. 

For intermediate and poor risk patients, their therapy really needs to include an IO treatment. For the most part, that IO therapy presently is either ipilimumab, nivolumab or axitinib, pembrolizumab. Axitinib, avelumab has not shown a survival benefit. It is unclear as to how effective it is when compared to its cousins. It is therefore not widely used. There are, however, also several breakthrough combinations that follow on the heels of those others. They include cabozantinib and nivolumab, which have been shown to cause improved response, progression-free and overall survival compared to sunitinib. It has been presented at our meeting and we’re awaiting, hopefully, regulatory approval for that, as well as a peer-reviewed publication.

Recently, there was a press release for positive outcomes from the CLEAR trial, which compared lenvatinib, pembrolizumab, and lenvatinib, everolimus, 2 significant first-line treatments. It looks like the IO/TKI therapies have a lot of activity, are closely related, and support each other in terms of the results of these trials.

For patients who are at poor and intermediate risk, then, it comes down to a question of whether we should pursue IO/TKI therapy, or IO/IO therapy. There is no one side to this; some people support one, while some people support the other. For intermediate and poor risk patients, in general, my choice is ipilimumab, nivolumab, because of the fact that we have longer follow-up time frames and more assurance in relation to the data. The survival benefit has been sustained for a long time. The last assessment was a minimum of 42 months. 

Some of the responses are durable, and we are seeing complete responses. There seems to be a leveling off or a tailing of the curve, a flattening of the curve, as one goes out in the months following treatment. We may see the same thing with TKI/IOs, it awaits longer follow-up. There are some patients, though, for whom TKI/IOs are very useful and are preferable. That takes into account that those combinations are associated with universally high response rates. In the case of some patients, if they appear that they’re going to have a clinical deterioration and run into trouble in the short run, there is more assurance that an IO/TKI would work. Mechanism of action is key for RCC, high response rates, and it allows us to avoid the early IO-related toxicity that we see with ipilimumab, nivolumab that can cause us to pause therapy. For patients who are rapidly progressive, there is a degree of assurance in using IO/TKI.

mRCC Risk Assessment and Treatment Options

Risk assessment is something where we talk about the qualifications of a patient. I think our approach or how we see most of our patients and the results of the clinical trials represent how we conduct risk assessments. Most of our patients are going to have a risk that will either be a symptom of their disease, time from diagnosis to treatment, or a laboratory abnormality. With those risk assessments, we define these patients to be of intermediate risk. 

We now have a multitude of first-line options for patients. The risk assessment should be incorporated from the beginning. When we discuss how we take care of patients, conforming to our data from clinical trials and then applying them to what I see in my clinic, there is a very similar pattern when one practices. One anticipates the benefit and tolerability of systemic therapy.

Our patients do not receive cookie-cutter treatment. We do not believe that all therapies are the same, nor are all of our patients the same. I would endorse having patients enroll in clinical trials. I think there is a benefit about further selecting our patients, and that is going to be always important. We do not yet have a biomarker or a way of assessing which therapy is beneficial for patients.

The risk assessment models give us a clear-cut advantage when approaching our patients with not only first-line therapy but subsequent therapies as well.

When we approach our patients during consultations, the first visit is always the most impactful one. It is important to not only approach our patients regarding the new diagnosis and how we can take care of it, but we must also discuss the goals of therapy for a disease that has a moderate response in a dramatic fashion. Most of our patients will have a partial response. Our goals with therapies are to, of course, shoot higher.

Looking back at the usage of high-dose IL-2 [interleukin-2] and immunotherapy back in the 1990s—though small, less than 10%—complete remission seemed to be the ultimate goal. Patients who received high-dose IL-2 in clinical trials, in the data that analyzed this, even in the SELECT clinical trial, one was able to assess not only the patients who had complete remission, but also a good partial remission. The durability of these therapies is important as well. 

We must be idealistic and think about the complete remissions. We must think about the possibility that we may be able to have our patients receive therapy and then come off therapy, and actively monitor them. We still approach them with better tolerability in mind, as well as efficacy approaches that utilize agents including oral tyrosine kinase inhibitor therapies. 

We like to think about utilizing efficacious therapies with tolerability. The same approach applies to our immunotherapies. Toxicities can be so variable, yet we have to be aware of, again, taking care of a patient who has a cancer rather than the cancer itself. But we should remain idealistic when defining our treatment goals with the patient. 

We like to think about long-term overall survival; 25 years ago, using high-dose IL-2, survival was probably less than a year. Fast forward to what we have in 2020, going into 2021, our overall survival rate should be close to 5 years. Despite the fact that we are looking for scans to show regression or complete remission, sometimes we have to explain to a patient that no change or stable disease can still be a positive response. 

I described to a patient today how we put them on a certain therapy, and they were disappointed that the disease did not change. Yet, I explained to the patient that, “For the last 6 months, your disease was growing steadily each month. And now suddenly, on therapy, your disease is not growing at all.” That defines a change. 

We try to have these conversations with patients early. We must allow patients to understand that our goals are the same as their goals: elimination of the disease with excellent quality of life. We should have a conversation about overall survival, but we should definitely try to have a conversation about complete remissions as well.

Treatment Planning and Risk Assessment in mRCC 

Surgery has been the cornerstone of management for kidney cancer. Surgery largely has a role in that it is utilized for either nephrectomy or a partial nephrectomy for localized kidney tumors. Those are the curative treatments for a localized kidney tumor. For people who have metastasis, cytoreductive nephrectomy has been utilized widely to remove the kidney primary before starting systemic therapy. There was a large, randomized trial, called CARMENA, that randomized patients to a cytoreductive nephrectomy followed by sunitinib versus sunitinib alone. It was a noninferiority trial. It showed that the survival was the same for patients regardless of whether they had the cytoreductive nephrectomy. 

Now this conflicted with 2 older trials in the interferon era that showed that patients lived longer if they had had a cytoreductive nephrectomy in the setting of interferon. It has caused us to pause and reevaluate the role of a cytoreductive nephrectomy. It is clear that patient selection is key in choosing cytoreductive nephrectomy. Patients with poor risk tumors, comorbid conditions, wide-spread metastasis in the bone, and those who are symptomatic are likely not good candidates for cytoreductive nephrectomy, based on the CARMENA trial. For patients with large kidney tumor primaries, particularly if they have symptoms with hematuria and a very small metastatic burden, like nodules in lungs, should still undergo a cytoreductive nephrectomy. 

Surgery also plays a role in managing metastasis. If there’s a solitary metastasis, and it can be removed without excessive morbidity, then the metastasectomy is still one of our key tools in the treatment of metastatic renal cell cancer. An example of that would be a patient who has a nephrectomy and then 2 or 3 years later develops a growing lung nodule. In that case, resectioning of that lung nodule is important for diagnosis and management. Also, orthopedic surgery is used for patients who have pathologic fractures or who progress in areas such as the bone or spine, despite radiation therapy. Then surgery is utilized for those patients as well.

When considering how we can improve outcomes in surgical patients, we have to have a good rapport with our urologist. The conversation in the past was always about cytoreductive nephrectomies followed by systemic therapies. The clinical trials revealed a possible benefit to single-agent tyrosine kinase inhibitor therapies as well as the potential benefit of utilizing immunotherapies as a neoadjuvant therapy to allow the patient to have a resectable disease. Thus, we have to approach the situation, when it comes to surgery, making sure that we realize that surgery can be a necessity prior to initiation of systemic therapy.

That may be based upon symptoms, including hematuria, pain, and vascular compromise when it comes to tumor thrombus. The usage of a multidisciplinary care team is of significant importance. At the same time, there is still conversation regarding the possibility that we can reduce the tumor burden in patients and have the patient undergo nephrectomy, but suddenly conclude that the patient may not need to be initiated on systemic therapy so fast.

Clinicians should be cautious with surgery, specifically in regard to the location of the tumors. Right-sided tumors mean potential liver involvement. Left-sided tumors can involve the celiac or the superior mesentery vasculature, bulky retroperitoneal disease, poor functional performance status, comorbid conditions. All these things should be taken into account prior to and after surgery. An improved surgical outcome would be quite important to our patients, again thinking about it in a sequencing fashion.

Supportive Care for mRCC: Current Practices

There has been rapid transition and progress in our first-line therapy for clear cell carcinoma. Before the advent of tyrosine kinase inhibitors [TKIs], there was very little to offer patients with metastatic renal cancer. The median overall survival was less than a year. For many years, there were very few options, but that really changed as a result of a better understanding of tumor biology and the importance of the VHL gene and its mutation. There was also the development of drugs that targeted the downstream effects of that mutated gene. 

There have been a number of different tyrosine kinase inhibitors and mTOR inhibitors that were developed and revolutionized treatment, improved prognosis, expanded our therapeutic armamentarium. That development was beginning in 2005, with the regulatory approval for sorafenib. Recently, the last of these tyrosine kinase inhibitors to get approved in the United States was the lenvatinib plus everolimus combination. Even more recently, we’ve now included immunotherapy [IO] in the first line-treatment for RCC [renal cell carcinoma] with even more gains in efficacy. There has been a series of phase 3 trials that have compared these immunotherapy combinations to TKIs, and these trials have shown a benefit and received regulatory approval. 

For the most part, the 2 treatments that are used are ipilimumab/nivolumab and axitinib plus pembrolizumab. In deciding first-line treatment for patients, one question is, does that patient need systemic therapy immediately? 

There are a number of patients who present with small, asymptomatic metastasis. One of the features of RCC, historically, has been that the tumor can either progress rapidly or the tumors can be very indolent and slow growing. It is an unpredictable pattern of progression. For some patients, the best treatment is no treatment. We simply follow those patients with scans, and if it looks like there is a change in the progression pattern, then we implement systemic therapy. 

For other patients who need treatments, the best path is to look to see into what risk category those patients fit. For patients who have favorable-risk tumors, then there are different options. There’s tyrosine kinase inhibitor single therapy; there is a TKI/IO combination, pembrolizumab/axitinib; and there is IO/IO combination, ipilimumab/nivolumab. It is not that one shoe fits all. There are different pros and cons of each of those programs. These need to be taken care of while having discussions with patient, considering their individualized needs and recognizing the comorbid conditions. The patients who have intermediate- or poor-risk tumors may need therapy soon, although some intermediate-risk patients can likewise be followed for long periods. Following nephrectomy with metastasis, some of those patients do well for a long time. 

Again, the best path may be surveillance until therapy is needed. For intermediate- and poor-risk patients, when a systemic therapy is required, the options right now are either IO/IO therapy or IO/TKI therapy. There are some pros for one and cons for another, so it is really an individual decision by the physician that will best meet the needs of the patient. One of the factors that is involved here is that the different and new IO first-line programs have all been developed in parallel. They were all compared to sunitinib. We can make some cross-study comparisons and say, this looks better in this population and that looks better in that population, but since they were all developed in parallel, we really haven’t been able to compare them. They haven’t been compared to each other, which does cause a bit of a disadvantage when claiming one therapy is better than another.

When we sit and talk to our patient, we have already talked about their CT scans. We have talked about their cell type and possibly their surgical intervention prior to our visit. We then have to think about how we are going to approach our patients, whether we treat them using first-line therapy or active surveillance, which is sometimes an appropriate conversation. We talk about disease burden as well.

The first thing we have to try to do is have the physician undergo risk categorizations with our patients. Defining their risk is quite important. We have to take the patient, recognizing the concerns of the tumor itself. Is this a newly diagnosed disease? Is this fast-growing? Is the patient having symptoms? Is the patient’s functional performance status affected by this? We need to think about the emotional support the patient may have, patient compliance, if using oral therapies, and travel, depending upon the patient to come into our office for intravenous therapies, or even receiving oral therapies that require laboratory assessment or visits. Winter does bring some restrictions for some of our patients.

Some of our patients require family support for their transportation, so a defined patient quality is truly an important factor when it comes to assessing not only the treatment but also the patient themselves. The most important thing is discussing the patient’s performance status, symptoms, tumor burden, and extent of disease, which may define the patient’s treatment, visceral involvement, and which area is treated.

Does this patient have a small pulmonary nodules that may have been present for some time? Does this patient have liver involvement or bone pain? Every patient is different, so you cannot walk in with a cookie-cutter mindset that every patient who comes to your office who has a symptom gets a certain regimen. We have to be open-minded about not only the variety of therapies we have but the conversations you have with the patient as well. Including them in the conversation, defining their goals of therapy, and allowing them to recognize their therapies may be chronic is necessary. Alternatively, we can be a lot more aggressive and treat them with an immunotherapy combination that enables the patients to have fewer toxicities, or possibly durable remissions, where they can be observed off therapy.

The conversation regarding active surveillance is always important. Our patient populations who have nominal symptoms and have undergone a nephrectomy can have discussions about active surveillance. As a medical oncologist who takes care of patients with renal cell cancer, it is the hardest conversation to have when trying to convince a patient to opt for surveillance when they come to you saying, “I have an advanced or metastatic disease, and I was told to start therapy.”

This goes back to defining our goals. It is important that we have communication and a sense of appreciation to have a patient be educated. We now let them know how we think, and we have also started recognizing how, in the patient’s eyes, they want to have their therapies be as aggressive as possible for the elimination of disease with excellent quality of life.

Selecting Frontline Therapy for mRCC

 For patients in clinical trials who receive first-line therapy, there are defined criteria. They are called RECIST. If a person meets progression by RECIST, in the past those patients would come off that therapy and would get second or subsequent therapy. One of the things that we are realizing is that although there may be small growths in the tumor meeting RECIST criteria, sometimes there can be fluctuations in terms of the size or measurements of the tumor. Sometimes patients, even though there is a degree of progression, are still clinically benefitting from the medication. They may be feeling well on the medication and they may make slow progression. 

The choice of stopping a first-line treatment and going to second-line treatment is dependent on the relative rate of progression, whether the patient is symptomatic, how they were doing in terms of feeling on the first study, and if there are good options for second- or third-line therapy. For patients who have been treated with sequential therapies in the past, if there really is not another good option for those patients, we generally continue the program for as long as we can, as long as they’re feeling well. When going from a first-line therapy to subsequent therapy in RCC [renal cell carcinoma], for the most part, the paradigm has been defined for people who are treated with tyrosine kinase inhibitors [TKIs], like sunitinib and pazopanib, in first-line therapy, because that’s where the evidence lies. Nivolumab, cabozantinib, axitinib, lenvatinib/everolimus all show benefits in that setting and are approved in second- or third-line therapy. Now, the situation has changed. 

Now, monotherapy with TKIs is not used for the majority of patients in first-line therapy. Now it’s IO [immunotherapy] combinations. It has left us with the question of what to do when people progress on an IO combination as a second- or third-line therapy. Studies need to be done to define what the optimal therapy is there. It is clear that, for patients who have progressed on ipilimumab/nivolumab who haven’t been treated with a VEGF-targeted therapy, there is good activity for most of the VEGF-targeted therapies in that setting. Certainly cabozantinib, axitinib, and lenvatinib/everolimus are good candidates for a patient who progressed on ipilimumab/nivolumab. We do not know what the best strategy is for the patients who have had a TKI in the first-line setting, the patients who have progressed on axitinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab. We really do not have good data about the best way to treat those patients. In clinical practice, for the most part, the practice has been dominated by switching to a different TKI. 

If a patient has progressed on axitinib/pembrolizumab, we might use lenvatinib/everolimus or cabozantinib. But the question is, is there a role for IO therapy for those patients? Why are we choosing a second-line TKI and not another IO therapy? That needs to be addressed with clinical trials. There has been one large, single-arm experience where over 100 patients were treated with lenvatinib/pembrolizumab in that setting. People had progressed on an earlier IO, and in that series, the response rate was over 50%. There was long progression-free survival. It looks like there may be a benefit for IO/TKI therapy in the subsequent rounds of treatment for people who have progressed on first-line IO therapy.

There is a randomized clinical trial, the CONTACT study, that is addressing that issue. It compares cabozantinib/atezolizumab versus cabozantinib. We need to further tease out which patients seem to benefit from an IO/TKI therapy based on their prior response and their prior agents. It is also an area where we need to look for novel drugs. There is a new novel drug, a HIF [hypoxia-inducible factor] inhibitor, that is from Merck & Co, Inc. That is a drug that showed activity in heavily pretreated patients. Looking for a drug that uses a novel mechanism of action is important also.

When choosing second-line therapy, we have to always think about what the patient received as first-line therapy. Historically, looking at sequencing when we only had options of TKI therapy, it was relatively simple. In 2007 to 2009, we had the introduction of mTOR inhibitors. It was an easy sequence of a TKI, to an mTOR, back to a TKI. There were questions of a TKI, followed by TKI, followed by an mTOR. 

In 2015, we had the introduction of using immunotherapy, that being nivolumab, as a second-line therapy. It became easier to use nivolumab as a second-line therapy now that we are using immunotherapy. So the first-line agent, it is important to recognize that the second-line therapy and subsequent therapies will be based upon the patient’s response to what they received as first-line therapy. Tolerance is quite important as well.

It does get a little confusing if your patient has toxicity to a combination therapy, especially if you are trying to eliminate one and continuing the second. Then you start going on disease progression as a guide to how to think. Going back to data gives some insight. There are still not much data in regard to sequencing therapies, and that is where the art of practicing oncology for the patient with renal cell carcinoma is quite important.

mRCC: Moving to Second-Line Therapy

 When patients present to me and they are of intermediate or poor risk, I still have to go back to the days of high-dose IL-2 [interleukin-2] in trying to achieve a complete remission in our patients, where our therapies can actually be quite tolerable and durable. If patients are appropriate candidates, without contraindications to receiving immunotherapy [IO], I like to treat our patients at the John Theurer Cancer Center with a combination of ipilimumab/nivolumab, then sequence to nivolumab after the 4 doses of ipilimumab/nivolumab combination.

It gives us the ability to have our patients come to the office. We can monitor the patients. Tolerability seems to be quite good. Patients are having an enjoyable time out of the office. Oral therapies may be beneficial. However, I do get concerned about some of the chronic toxicities of oral therapy, not only the physical toxicities, but also the financial toxicities.

There’s a presentation at the International Kidney Cancer Symposium that discusses the cost of the agents in combination. It appears that the combination of IO/IO, or ipilimumab/nivolumab, seems to be almost $100,000 cheaper over the course of a year compared to using IO/TKI [tyrosine kinase inhibitor] therapy. In this time of the year, when the Medicare drug plan donut hole might be quite concerning to patients, out-of-pocket expenses may be significant. It is important to recognize the financial toxicities as well.

Nazir Tannir, MD, presented information on the CheckMate 214 trial at the American Society of Clinical Oncology Genitourinary Cancers Symposium in 2020. This involved looking at the 59 patients who were in a complete remission. There were percentages of patients who had been taken off therapy, who were now on active surveillance post-therapy, who remained in a complete remission years after receiving therapy. Some patients had to come off the study because of toxicity and remained off therapy, still in a complete remission. 

Our goals when providing treatment are having patients experience improved quality of life, long-term survival, complete remissions, or partial remissions that are durable, where patients can remain off therapy. In the appropriate patient population, ipilimumab/nivolumab seems to be an excellent first-line therapy.

If the patients are have having a more aggressive disease, visceral involvement, or disease that needs reduction because of patient symptoms in a short period, I would use the combination of axitinib and pembrolizumab as a first-line therapy. Tolerability is excellent. Axitinib’s short half-life allows us to adjust doses based upon toxicity. We have become very familiar with utilizing immunotherapy, and after evaluating the response or efficacy data on the KEYNOTE-426 trial, one feels very confident patients should have not only good tolerability but effective therapy as well.

Second-line therapy all depends on first-line therapy. If the patient received IO/IO as first-line therapy, we consider using the single agent cabozantinib. If the patient received axitinib/pembrolizumab and had recent, dramatic disease, I would consider using lenvatinib and everolimus as a second-line therapy. There is still the ability to utilize immunotherapy as a third line.

In terms of the standard management for RCC [renal cell carcinoma], as newer drugs were studied and found to be effective, most treatment plans consisted of sequence therapy, where we treat a patient with drug A to maximum benefit, and then when the patient progresses, go to drug B, and then go to drug C. That sort of scenario was comprised of patients treated with TKIs or mTOR inhibitors. One of the points that has not been appreciated is that some of the studies that showed a benefit for sequence therapy, for say drug C, seemed to provide a small benefit. But in the conglomerate, when we started out with drug A, then drug B and then went to drug C, the benefits for the patient were fairly dramatic overall, with improvement in survival and good quality of life over the period of the treatment. Now, with the advent of IO therapies, our paradigm has been changed, and that is going to need to be revisited in defining what the paradigm is for sequencing therapy, since IO treatments are really one of the 2 main types of treatments we use to treat advanced RCC.

Second-Line Treatment Approaches for mRCC

 Lenvatinib is a highly potent VEGFR inhibitor. It hits multiple kinases. In addition to hitting a VEGF receptor, it also targets FGF. The fibroblast growth factor receptor was proposed as a kinase that is important in overcoming resistance to VEGF-targeted drugs, which we refer to as angiogenic escape. When lenvatinib was initially developed, there was interest and further study in this compound in patients who were more resistant or refractory to some of the other earlier TKIs [tyrosine kinase inhibitors] like sunitinib and pazopanib because of that mechanism of action. 

There was interest in combining it with an mTOR inhibitor. It was largely based on preclinical data that suggested that when lenvatinib was combined with an mTOR inhibitor, the activity was enhanced. My colleagues and I designed a study that looked at lenvatinib and everolimus together in a phase I setting as a lead-in to define the dose in that setting. Then, we moved onto a randomized phase 2 trial where the combination of lenvatinib and everolimus was compared to the lenvatinib monotherapy and to everolimus. In the lead-in, we found that the recommended dose for lenvatinib/everolimus was 18 mg of lenvatinib a day and everolimus 5 mg a day. 

The trial was then conducted, and there were about 150 patients accrued to that trial. We used everolimus as the control arm because, at the time, everolimus was the most commonly used second- or third-line therapy for this disease. In this trial, both lenvatinib/everolimus and lenvatinib had higher response rates and longer progression-free survival than everolimus. The magnitude was greater with the combination. Although there were some trade-offs, in terms of adverse events, the adverse effect profile of lenvatinib/everolimus was quite manageable. The main adverse effect that was observed was diarrhea. 

One of the goals or one of the postulates for the lenvatinib story is that it is better to go in with a high dose and hit the tumor hard. If there then are adverse effects, back off with dose reductions. Most of the lenvatinib studies in RCC [renal cell carcinoma] have shown a fairly high rate of dose reduction, about 60%. The idea is to go in with a high dose for efficacy, and then if there are safety issues, back down on the dose. That was the idea behind that particular program. In an updated analysis, there appeared to be a survival benefit for lenvatinib/everolimus based on that small, randomized phase 2 trial.

The combination received regulatory approval based on the overwhelming efficacy that was seen in a randomized phase 2 trial. It is an important combination. Lenvatinib is a very potent, effective TKI. The addition of an mTOR brings in another mechanism of action, particularly in patients who have progressed on first-line TKIs. There is a sense of comfort for us when using the combination, not only with another TKI, but as well as a drug with different mechanism of action, like the approved drug everolimus. It is a highly effective combination that is approved for patients who have progressed previously on a TKI. 

It was because of that efficacy and because it was approved on a relatively small phase 2 trial that the phase 3 followed. In the large phase 3 trial, the comparison was between lenvatinib/pembrolizumab to lenvatinib/everolimus, now in first line, to sunitinib. The results of that trial will be available shortly. There also looks to be a role for lenvatinib/everolimus now in the new era of IO [immunotherapy]. One of the concerns for patients who have progressed on first-line IO/TKI therapy combinations like axitinib/pembrolizumab is just giving them another TKI. How much better will the TKI be than the combination? There is a level of comfort with lenvatinib/everolimus bringing in the mTOR component. It is really a regimen that is defined on efficacy. I would see more use for that combination in the new era when the first-line paradigm has changed.

Treatment Options in Metastatic Renal Cell Carcinoma | Insights

Renal Cell Carcinoma and Novel Therapies

Supportive Care and Systemic Therapy for RCC

Supportive Care and Systemic Therapy for RCC

Newly Diagnosed RCC: Treatment Planning

Risk Stratification in Renal Cell Carcinoma

mRCC Risk Assessment and Treatment Options

Treatment Planning and Risk Assessment in mRCC

Supportive Care for mRCC: Current Practices

Selecting Frontline Therapy for mRCC

mRCC: Moving to Second-Line Therapy

Second-Line Treatment Approaches for mRCC

Lenvatinib for mRCC