Recent Trial Updates in Advanced Renal Cell Carcinoma (RCC)

In the advanced renal cell carcinoma treatment space, ongoing trials are utilizing and expanding upon the current treatment armamentarium. In this Precision Medicine Perspectives series Recent Advances in the Management of Advanced Renal Cell Carcinoma (RCC), Chandler H. Park, MD, a genitourinary oncologist, details recently updated data on therapies for advanced renal cell carcinoma and explores how they impact treatment paradigms.

Targeted Oncology™: What do the NCCN [National Comprehensive Cancer Network] Guidelines recommend for frontline and subsequent treatment of advanced clear cell RCC [renal cell carcinoma]? How do these recommendations differ by a patient’s risk status?

Dr Park: I start with the risk score that we use: the IMDC [International Metastatic RCC Database Consortium] Criteria. It’s based on various factors: whether the time from diagnosis to systemic therapy is less than a year, Karnofsky performance score of less than 80%, and hemoglobin less than 12 mg/dL. Additional factors assessed by the IMDC Criteria include: corrected calcium that’s above the upper limit of normal—typically about 10.2 mg/dL—and neutrophils, the white blood cell count within ANC [absolute neutrophil count], for which the upper limit of normal is typically between 2 to 7 per microliter [µL] and it can go up to 10 per µL. Typically, I use a neutrophil count between 4.5 to 10 per µL. If it’s above 10, that’s considered a score, along with a platelet count of 150,000 to 400,000 per µL. If they have none of those factors, that’s considered favorable risk. If they have 1 to 2, that’s called intermediate risk. Three or more of those factors is considered high risk.

What do the NCCN Guidelines do with these different risks? If it’s a favorable risk with zero risk, there are 3 preferred regimens in the NCCN Guidelines: axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab. If patients have 1 to 2 risks or 3 or above, they’re lumped together in the poor and intermediate risk in the NCCN Guidelines. The treatment options are axitinib-pembrolizumab, cabozantinib-nivolumab, lenvatinib-pembrolizumab, and ipilimumab-nivolumab, which is unique because it isn’t an option for favorable risk.

How do I treat based on the patient’s risk status? If they have favorable risk, I use a TKI [tyrosine kinase inhibitor] and an immunotherapy. Based on the patient’s profile, I’d consider cabozantinib-nivolumab, pembrolizumab-axitinib, or pembrolizumab-lenvatinib. If they have poor or intermediate risk, I ask myself, is the patient very symptomatic? Do they need treatment right now? As an oncologist, I have to decide whether I need to get the cancer under control. If that’s the case, I like to use a TKI and an immunotherapy regimen. My preferred regimen is lenvatinib and pembrolizumab because it has the highest response rate and the highest complete response [CR].

Alternatively, if we have some time and the patient isn’t really symptomatic, I’d consider nivolumab and ipilimumab for a select patient population because CheckMate 214 was the first study [to investigate the efficacy and safety of first-line nivolumab and ipilimumab]. In this study, there’s a patient population that show durable PFS [progression-free survival], so I’d consider that for some of my patients.

Targeted Oncology™: Describe the updated efficacy results from the CLEAR study of lenvatinib and pembrolizumab.

Dr Park: This phase 3 study was presented at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] last year by Robert Motzer, MD. The key eligibility criteria included advanced clear cell disease, treatment naive, and a Karnofsky [performance] score greater than 70. There were 3 treatment arms. One arm was lenvatinib at a 20 mg PO [per orally] QD [daily]—which is different from the typical lenvatinib arm that we’re used to, which is 18 mg—and pembrolizumab at 200 mg IV [intravenously] q3weeks [every 3 weeks]. The second arm was lenvatinib at 18 mg daily and everolimus at 5 mg oral daily. The third arm, which has been a common standard comparison arm for all these studies, was sunitinib at 50 mg orally daily. The primary end point for this study was progression-free survival.

The phase 3 CLEAR study had a median follow-up of 33.7 months and results showed an improvement based on different factors, such as poor risk, intermediate risk, and favorable risk. The hazard ratio [HR] for poor risk patients was a very strong, with an HR of 0.18 (95% CI, 0.08-0.42). For intermediate risk, the hazard ratio was 0.46 (95% CI, 0.35-0.60). Favorable risk patients demonstrated a hazard ratio of 0.43 (95% CI, 0.29-0.64) and an overall hazard ratio of 0.42 (95% CI, 0.34-0.52).

Targeted Oncology™: What were the health-related quality-of-life outcomes from the same study?

Dr Park: One of the things that they updated is the health-related quality-of-life outcomes that was published in The Lancet Oncology by Dr Motzer. They looked at the results from the phase 3 CLEAR study and compared them to sunitinib with the health-related quality-of-life outcomes. They evaluated such things as functional index and disease-related symptoms. They also did a questionnaire, including the European Organisation for Research and Treatment of Cancer Quality of Life [EORTC QLQ-C30], and the EQ-5D-3L [European Quality of Life 5 Dimensions 3 Level], which is a very accurate measure of health care quality of life. The health-related quality-of-life results demonstrated that patients given lenvatinib plus pembrolizumab had similar or exceeding scores compared with patients given sunitinib. These results support not only the efficacy and safety of lenvatinib-pembrolizumab, but that it appears to be the same if not better than sunitinib.

Targeted Oncology™: Can you discuss the results of the CheckMate 9ER trial of cabozantinib and nivolumab that were presented at ASCO GU 2023?

Dr Park: CheckMate 9ER is another first-line metastatic renal cell carcinoma study. In this study, the key inclusion criteria were very similar: untreated patients, metastatic renal cell carcinoma, clear cell component, and any IMDC risk group, including favorable risk. They randomized the patients into nivolumab 240 mg IV q2weeks [every 2 weeks] with cabozantinib 40 mg. The comparison arm was sunitinib at 50 mg daily. The primary end point was progression-free survival, with secondary end points including overall survival (OS) and objective response rate (ORR). In the updated PFS data at a 33-month median follow-up, they found a clear separation, with a hazard ratio of 0.56 (95% CI, 0.46-0.68) in the Kaplan-Meier curve, which equates to a 44% reduction in disease progression. As a reminder, at the 24-month mark in the study group with nivolumab and cabozantinib, the PFS was 39.5% vs 20.9%. The study group demonstrated a progression free survival of 70.3% at 24 months compared with 60.3% in patients treated with sunitinib [HR 0.70 (95% CI, 0.55-0.90)], which is a 30% reduction in death.

Targeted Oncology™: Taking all these data updates together, how might they impact your treatment approach for patients with advanced clear cell RCC?

Dr Park: In my practice, we choose a regimen that we’re very comfortable with. As president of the Kentucky [chapter of] ASCO, I know some of my colleagues may be very familiar with other regimens. With that said, if I have a very symptomatic patient who is very young, my preference is to do pembrolizumab and lenvatinib because it has the highest complete response rate and the highest [overall] response rate. That allows me to get the patient’s cancer under control. One in 20 patients on pembrolizumab and lenvatinib show progressive disease in their first scan at 3 months. Compare that with nivolumab and ipilimumab, where 20%—1 in 5 patients—progress. For some patients, if you give them nivolumab and ipilimumab, they may be too weak to get second-line treatment.

There are other risk factors in patients that I consider such as having a cytoreductive nephrectomy in which a very small patient population benefit. Patients who had a cytoreductive nephrectomy didn’t show overall improvement based on results from the CARMENA study. However, there are select patient populations that are symptomatic and have hematuria under control. In this case, you would consider something like pembrolizumab and axitinib, where you can maybe do 1-3 cycles, try to get their cancer under control, and then do cytoreductive nephrectomy. For most patients, I wouldn’t consider cytoreductive nephrectomy. However, if I do consider cytoreductive nephrectomy, I would think about a pembrolizumab-axitinib combination.

In terms of nivolumab and cabozantinib, what do I consider in that patient population? Similar to pembrolizumab-lenvatinib, they both show quality-of-life improvement, which is something I think about. With cabozantinib, results tend to be a little more mature in terms of the bone data. A lot of our patients with metastatic clear cell renal cell carcinoma also have metastases in the bone. I would consider cabozantinib-nivolumab an option for patients based on CABOSUN [study] and lenvatinib-pembrolizumab based on updated data from the CLEAR study, which also shows activity for patients with metastatic cancer to the bone.

Overall, how does the evolving clinical data with these trials impact my treatment? For symptomatic patients, I would consider the strongest medication, i.e., lenvatinib-pembrolizumab. I’d also consider the patients’ overall performance status and, as a physician, my eyeball test. If a patient is a bit frail or a little weaker, I wouldn’t consider pembrolizumab-lenvatinib as a frontline treatment because even though you get a higher complete response and higher [overall] response rate with that combination, there tends to be more adverse effects and toxicities. I would potentially consider starting at a lower dose in that specific patient population. On the other hand, I would also consider nivolumab and cabozantinib.

For patients who may not be symptomatic, there’s still a role for nivolumab-ipilimumab. I’m very excited about the PDIGREE study, which is run by different cooperative groups. In the PDIGREE study, you have patients who receive 4 cycles of nivolumab and ipilimumab, and if they progress, are then randomized to nivolumab-cabozantinib vs cabozantinib monotherapy. This field is slowly evolving. I still consider nivolumab-ipilimumab for some of these patients, and I’m eagerly awaiting the PDIGREE study to see if there’s any improvement in PFS and overall survival.

Targeted Oncology™: It looks like there were a lot of novel treatment mechanisms and molecular classification data presented at ASCO GU 2023. Can you talk about those, how they might change the field, and any other data or clinical trials that you’d like to highlight?

Dr Park: One of the things about ASCO is that there are always new medications slowly rising. One of the studies featured at ASCO was STARLITE 2. It was a phase 2 study of nivolumab plus lutetium-177 labeled anti–carbonic anhydrase IX [CAIX]. It’s a monoclonal antibody with girentuximab in patients with advanced clear cell renal cell carcinoma. The background in this study is CAIX, a cell surface glycoprotein expressed in up to 90% of patients with clear cell renal cell cancer, but typically rare in normal tissue. It provides a very sensitive target for metastatic clear cell renal cell carcinoma. This is also a very promising combination because we have lutetium-177 as a payload that is used for the combination.

This study focused on patients with biopsy-proven clear cell renal cell cancer with progressive disease after prior systemic therapy, including 1 or more IO [immuno-oncology] agents, such as pembrolizumab or nivolumab, adequate organ/ [bone] marrow function, and 1 or more evaluable lesions based on an (89)zirconium PET [positron emission tomography] scan. The treatment consisted of 177 lutetium–girentuximab every 12 to 14 weeks for a maximum of 3 doses plus nivolumab every 2 weeks until progressive disease.

While this study is just starting, I picked this study because it’s very unique as it combines a lot of different features. One, we use a checkpoint inhibitor backbone, in this case nivolumab. Second, you also have a lutetium payload of 177-girentuximab. And third, 90% of patients with metastatic renal cell cancer have the CAIX cell surface glycoprotein. That’s one study that I’m very excited about.

Another study that I’m very excited about is CaboPoint, a phase 2 study of cabozantinib after checkpoint inhibitor therapy in patients with renal cell cancer. This study looked at cabozantinib with 2 independent cohorts. One is vascular endothelial growth factor [VEGF]–targeted therapy. This is emerging for patients who progress with renal cell carcinoma after a checkpoint inhibitor. Overall, if a patient receives an immune checkpoint inhibitor-based therapy and progresses, we don’t have data that suggests re-challenging with an immune checkpoint inhibitor. As a result, this area is in flux.

One of the studies with cabozantinib and atezolizumab is maturing. Another study is evaluating nivolumab and tivozanib. As mentioned previously, CaboPoint, a phase 2 study, is evaluating cabozantinib after checkpoint immunotherapy. This area of research is rapidly improving. The key question is, are we going to continue with immune checkpoint inhibitors, like we do in metastatic colorectal cancer—where you continue with bevacizumab after first- and second-line treatment?

Targeted Oncology™: What are the remaining unmet needs for patients with advanced clear cell RCC, particularly those who have disease progression on the available systemic therapies?

Dr Park: We really need a biomarker in metastatic clear cell renal cell carcinoma. In talking with different GU oncologists, we’ve noticed that metastatic clear cell renal cell carcinoma is a very heterogeneous group. We tend to overclassify patients into 2 separate groups. One group is known as an angiogenic-driven metastatic renal cell cancer. Those are the angiogenic renal cell cancers that are driven by angiogenesis. For this group, the medications that tend to work best are sunitinib as well as cabozantinib, lenvatinib, and axitinib.

You also have a second group of metastatic renal cell cancer called immunogenic, which tends to be inflammatory. These metastatic renal cell cancers tend to respond best to immunotherapy. Brian Rini, MD, at Vanderbilt University is conducting a clinical study called OPTIC RCC. They’re looking at the mRNA sequence to see which of these patients may benefit more from angiogenic-targeted medication combination, such as nivolumab-cabozantinib or lenvatinib-pembrolizumab. Another group evaluated in this study is based on the mRNA sequence that’s specific for every patient unique with a diagnosis of metastatic clear cell renal cell, whether they have an immunogenic marker. That means that they would benefit more from nivolumab and ipilimumab.

We do have 1 specific biomarker: sarcomatoid. If a patient has had metastatic clear cell renal cell carcinoma but also have sarcomatoid features, some data shows that they have up to a 20% to 25% response rate with nivolumab and ipilimumab. If I have a patient with metastatic clear cell renal cell carcinoma who has sarcomatoid features, I consider nivolumab-ipilimumab as my No. 1 choice.

In terms of continuing treatment after first line, this always changes based on the newest information. If I start patients on nivolumab and ipilimumab, I would go with a TKI in the second line. If a patient progresses on cabozantinib, I would go to tivozanib in the third line. If I start a patient on nivolumab and cabozantinib and they progress, I would consider lenvatinib and everolimus in the second line. And if they progress on that, I would put them on tivozanib. If a patient starts with lenvatinib-pembrolizumab in the first line, I would consider cabozantinib monotherapy in the second line and then I’d consider tivozanib in the third line.

The fourth piece of the puzzle is if I have a patient who progresses on pembrolizumab and axitinib. I can go with cabozantinib or I can go with lenvatinib-everolimus, which is based on performance status. In my practice, I have found that cabozantinib tends to show more sinus and GI [gastrointestinal] symptoms. Lenvatinib and everolimus tend to have more mucositis. Regardless, if they progress on lenvatinib-everolimus or cabozantinib in the second line, I would consider tivozanib in the third line.

Lastly, we have a lot of clinical studies here at Norton Cancer Institute. We have a study comparing pembrolizumab-lenvatinib with an HIF-2 alpha [hypoxia-inducible factor-2 alpha inhibitor]. We also have a study evaluating an HIF-2 alpha [inhibitor] in the second-line setting. In terms of standard of care, that is my algorithm right now.