Transforming Treatments in Non-Clear Cell Renal Cell Carcinoma

In the non-clear cell renal cell carcinoma [nccRCC] research space, clinical trials have been shifting treatment paradigms and providing new ideas for investigation. In this Precision Medicine Perspectives series “Recent Advances in the Management of Advanced Renal Cell Carcinoma (RCC)”, Chung-Han Lee, MD, PhD, a genitourinary oncologist at Memorial Sloan Kettering Cancer Center, discusses the evolving treatment landscape, how the data shape treatment decisions, and the future directions of treatment.

Targeted Oncology™: Could you please provide a brief overview of non-clear cell renal cell carcinoma, including its prevalence, typical patient profile, and prognosis?

Dr Lee: Non-clear cell kidney cancer represents a very diverse set of histologies that are essentially defined by not being clear cell kidney cancer. Clear cell kidney cancer makes up between 60% and 80% of the possible cases, which is defined by alterations and loss of VHL [von Hippel Lindau]. As a renal cortical tumor, anything that can arise is collectively considered non-clear cell. This histology is quite diverse and can include things like papillary kidney cancer, which is often thought of as the second most common, followed by chromophobe histologies, followed by unclassified.

Unclassified seems like a misnomer, but it is literally the name of the classification scheme. There are also some smaller entities that have been associated with specific mutations, including FH [fumarate hydratase] deficiency, loss of NF2 or alterations within NF2, and medullary kidney cancer, which is a very distinct entity in and of itself. Medullary kidney cancer is associated with loss of INI1 or SMARCB1. These specific entities all have very different types of histologies that can be associated with it, and pathologically and molecularly look quite different from each other.

In terms of stratification schemes that we use, the classification of non-clear cell is mostly based on histology. For risk stratification groups in clear cell, including both IMDC [International Metastatic RCC Database Consortium] risk and MSKCC [Memorial Sloan Kettering Cancer Center] risk, those clinical stratification schemes are better validated within clear cell kidney cancer. Even though they have been applied to non-clear cell, the non-clear cell studies have been relatively small. Results from those studies are often reported but don’t have the same degree of stratification power that we see in clear cell.

In terms of thinking about other prognostic factors that may be associated with non-clear cell, it comes down to the molecular drivers of these diseases. There’s quite a bit of heterogeneity between all these cohorts. As a result, this makes a lot of the clinical trial comparisons quite difficult. We often have to evaluate these clinical trial results themselves, in which cross-trial comparisons are incredibly difficult for this population.

Targeted Oncology™: What are the current recommendations in the NCCN [National Comprehensive Cancer Network] Guidelines for patients who are not candidates for resection?

Dr Lee: Within the NCCN Guidelines, for anyone who is a candidate for resection or some sort of definitive therapy, we would consider surgical removal of localized disease to be the standard of care. However, it’s often the case for patients with non-clear cell kidney cancer that surgical removal is not possible or there is evidence of metastatic disease. In the adjuvant setting, there is not data for adjuvant therapy in non-clear cell kidney cancer. All those studies were done within clear cell. So, for post resection, the standard of care would be just observation.

For patients who have metastatic disease, the NCCN Guidelines are quite broad and somewhat nonspecific in terms of the recommended regimens. It divides treatments into preferred regimens and other useful regimens. The No. 1 preferred regimen for non-clear cell kidney cancer, given its rarity and relatively small size, is clinical trial. If there is a suitable study, we often consider patients for a clinical trial. However, other preferred regimens for non-clear cell include cabozantinib and sunitinib as reasonable options. Several other regimens are considered, including cabozantinib plus nivolumab or lenvatinib plus everolimus, and pembrolizumab and nivolumab monotherapies.

Targeted Oncology™: In your practice, is there a particular subgroup of patients that may be best suited for clinical trials versus other treatment regimens?

Dr Lee: One thing that’s very important to remember for non-clear cell kidney cancer is that it is a malignancy that tends to behave aggressively and overall is less responsive to systemic therapy. Performance status and how sick the patient is become critical for determining whether they would be a good clinical trial candidate, as many of these patients may not tolerate the entire screening process for a clinical trial. While it’s incredibly important and perhaps the most ideal thing for patients to be enrolled on a clinical trial, when they have non-clear cell kidney cancer, we also have to balance the time it takes for them to be put on protocol. The patient’s performance status and other clinical factors become critical in this setting.

Targeted Oncology™: Could you provide a brief overview of the study design, patient population, and efficacy results of the KEYNOTE-B61 study?

Dr Lee: The KEYNOTE-B61 study was an evaluation of lenvatinib plus pembrolizumab as frontline therapy in patients with non-clear cell kidney cancer. This is a companion study to the CLEAR study, which evaluated lenvatinib-pembrolizumab in the frontline setting in clear cell kidney cancer. Early data were reported at ESMO [European Society for Medical Oncology] Congress in 2020, in which 87 of the 147 patients were reported on, with about 59% of patients having papillary histology. Looking at the cohort of evaluable patients, they demonstrated an objective response rate (ORR) of 48% (95% CI, 36.4-58.9) and a 6-month PFS [progression-free survival] of 72% (95% CI, 60.7-81.0). What’s very notable when we think about non-clear cell is that this study is among one of the largest clinical trials available for non-clear cell kidney cancer. KEYNOTE-B61 offers a good look and characterization of this relatively heterogeneous histology, forming a very large cohort of patients.

In terms of thinking about some of the treatment-related adverse events associated with it, the most common with lenvatinib plus pembrolizumab include hypertension, diarrhea, and hypothyroidism. Most of these adverse effects can be managed with dose alterations. As with the clear cell regimen, the starting dose of lenvatinib is 20 mg by mouth daily. For patients who have unacceptable toxicities or cannot be managed with supportive care, lenvatinib is often dose reduced to 14 mg daily, followed by 10 mg daily, and then to 8 mg daily. Certainly, things like hypothyroidism or adrenal insufficiency, which can occur with immune checkpoint therapy, would require interventions such as thyroid hormone replacement or cortisol replacement.

Targeted Oncology™: Could you speak a little further about additional studies for non-clear cell RCC, such as SWOG 1500 and the phase 2 trial that you’ve contributed to?

Dr Lee: Within the non-clear cell space, there has been a lot of interest in understanding how we can pair biology to the various systemic therapies that are used. SWOG 1500 was recently reported in The Lancet in 2021. This was a 4-arm study trying to evaluate the role of MET inhibition in patients with papillary RCC, which has been thought to be a MET-driven malignancy. In this study, patients were compared against sunitinib. The 3 tyrosine kinase inhibitors that have MET activity are cabozantinib, crizotinib, and savolitinib. Both the crizotinib and savolitinib arms ended early due to lack of efficacy, so it later became a randomized trial of sunitinib vs cabozantinib, with 46 patients in the sunitinib arm and 44 patients in the cabozantinib arm.

They demonstrated an improvement, with an overall objective response rate of 23% vs 4%, favoring cabozantinib (p = 0.10). Additionally, patients receiving cabozantinib demonstrated a longer progression-free survival of 9.0 months compared with 5.6 months in the sunitinib group (95% CI, 6-12). The results translated to a hazard ratio of approximately 0.60 (95% CI, 0.37-0.97; p = 0.019). This is one of the few randomized studies we have for non-clear cell kidney cancer that demonstrated an improvement in progression-free survival and objective response rate, although the numbers remain relatively small. However, it’s very exciting to see these types of differences between the 2 treatment arms, underlying the need for MET inhibition for at least a subset of patients.

Another clinical trial is a phase 2, single-arm trial of cabozantinib plus nivolumab in patients with non-clear cell kidney cancer. In this study, patients were divided into 2 separate cohorts, the first cohort being a combination of papillary-unclassified and translocation-associated RCC. The second cohort was chromophobe kidney cancer. During this study, the chromophobe disease cohort was separated as chromophobe kidney cancer behaves differently from other histologies and tends to be less responsive to immune checkpoint inhibitors. The chromophobe cohort in this study ended early due to lack of objective responses.

Focusing mostly on Cohort 1, which is the papillary-unclassified and translocation RCC cohort, we demonstrated an objective response rate of 48% (95% CI, 31.5-63.9), with a median progression-free survival of 12.5 months (95% CI, 6.3-16.4) and a median overall survival of 28 months (95% CI, 16.3-NE). While we have a lot of experience using these medications in the clear cell setting, it becomes a little more challenging when we think about half-lives, because cabozantinib is a drug that has a relatively long half-life. Nivolumab, an immune checkpoint inhibitor, also has a long half-life. There’s a lot of work that needs to be done when it comes to the overlapping toxicities between these drugs and differentiating between which drug the adverse effects are associated with. Currently, it is standard practice to stop both drugs first. Once the toxicities resolve, you can attribute the toxicity to one drug or the other. This is often the most challenging part of treatment, with 2 drugs that have relatively long half-lives and overlapping toxicities.

Targeted Oncology™: Given the currently available treatment options, what are some unmet needs that future clinical research can address for non-clear cell renal cell carcinoma?

Dr Lee: It’s a very exciting time for non-clear cell kidney cancer, with the potential regimens and movement within this space. Right now, there’s a question of whether triplet therapy is going to be useful. The COSMIC-313 study in clear cell kidney cancer looked at cabozantinib plus ipilimumab plus nivolumab. The same type of study has been conducted in non-clear cell kidney cancer. For patients with very aggressive disease, we’re interested in seeing whether some type of triplet therapy may be helpful or if there will be too much toxicity associated with it.

The other thing we’re incredibly excited to see is the completion of the KEYNOTE-B61 study and understanding whether the objective response rate is going to be the same, higher, or lower. That’s going to be incredibly interesting to see, even though the initial study enrolled 80 patients and probably among the largest reported studies. When we get to the 147 [patient] range, this is a very robust cohort within non-clear cell, and with more extended follow-up. In that initial look, investigators could only report on the 6-month PFS rate. It would be very interesting to see what the median PFS would be for that.

Now that we have multiple single-arm studies, the other thing that will be very interesting to look at is the correlative analysis. We certainly have a lot of heterogeneity in the histologies that are going in, given the very different targets that are being hit. Even if objective responses look similar, they may represent non-overlapping populations. Understanding the degree of overlap or difference is going to be critically important. We’re very excited to see the correlative analysis that’s going to come out for some of these non-clear cell studies.

Interestingly, we’re starting to get some randomized protocols within the non-clear cell space. One of the things that has driven the development in clear cell kidney cancer is randomized clinical trials against the standard of care. In the past, that hasn’t historically been very feasible, and it has been very challenging to complete these studies. There are now new randomized protocols for non-clear cell kidney cancer, notably the SAMETA trial. This is a phase 3 study evaluating the role of MET inhibition in MET-driven RCCs. Savolitinib is a MET inhibitor paired with durvalumab, an immune checkpoint inhibitor. In this study, treatment is randomized against sunitinib. We also have another trial in the STELLAR-304 study, which compares zanzalitinib plus nivolumab versus sunitinib. The STELLAR-304 study is not a MET-driven protocol, however, it’s looking at patients with papillary-unclassified and translocation RCC and investigating whether a next-generation tyrosine kinase inhibitor with activity against both c-MET and VEGF will be superior against some of the earlier-generation drugs, like sunitinib.

Another thing down the line that may become interesting as we better understand some of the correlative analysis from the earlier studies is whether we can start doing molecularly directed protocols. The SAMETA trial that I mentioned earlier is a first look to see whether we can separate out that MET-amplified cohort. It would be very interesting to see a dedicated chromophobe protocol. As was noted in the cabozantinib-nivolumab phase 2 study, in chromophobe RCC, there was very little activity when this combination was used together. This represents a very unique histology in which specific therapies might be necessary. When we try to classify some of the unclassified RCCs, there are very distinct cohorts, including FH altered, NF2 altered, and MET amplified. Each of these distinct mutational profiles may respond to very different drugs. Down the line, I hope there will be more studies looking more specifically at those cohorts.

Targeted Oncology™: What clinical pearls could you offer to fellow oncologists for treating patients with non-clear cell renal cell carcinoma?

Dr Lee: Non-clear cell kidney cancer represents a very challenging population of patients due to its rarity. Getting at least a second opinion on the pathology is critically important. It’s often the case that we can see differences in what pathology read, even between different pathologists. Having a GU [genitourinary] pathologist with kidney cancer expertise is going to be very important.

The other thing to remember when we talk about non-clear cell kidney cancer is that sarcomatoid RCC is not specific to non-clear cell kidney cancer. Sarcomatoid is a variant histology that can be associated with any of the non-clear cell or clear cell RCCs. For example, there can be sarcomatoid chromophobe, sarcomatoid clear cell, or sarcomatoid papillary. We have to be very careful that we don’t automatically put sarcomatoid into the non-clear cell [RCC] basket, as some studies have done in the past. Because of the difficulty and aggressiveness of the non-clear cell histologies, in addition to pathology review, it’s also going to be very important to do some type of next-generation sequencing. Sometimes those mutations can provide additional information in our understanding how to think about this disease. Lastly, second opinions and discussion among multiple oncologists with experience are also critically important.