Combination therapies for patients with advanced renal cell carcinoma provides clinicians with new treatment avenues for their patients. To assess which path to go down, Tian Zhang, MD, MHS, and Randy F. Sweis, MD, led virtual discussions on evaluating patients’ risk criteria to determine their proper treatment.
REGIMENS COMBINING IMMUNOTHERAPY (IO) plus tyrosine kinase inhibitors (TKIs) are now established, preferred choices in the treatment of previously untreated patients with advanced clear cell renal cell carcinoma (ccRCC), unseating earlier single-agent targeted therapies as the standard of care in this space.
Multiple FDA-approved regimens mean patients and their care team have options when selecting the right therapy. However, picking an optimal regimen for each individual may require a limber approach and a careful look at the pivotal data.
A review of FDA actions in first-line RCC reveal a plethora of approved combinations that have become available over the past 5 years, the most recent being lenvatinib (Lenvima) and pembrolizumab (Keytruda), which was approved in August 2021 for the treatment of adult patients with advanced RCC in the frontline setting.1 Prior to that, 2 other IO/TKI regimens were approved for the same patient population, starting with axitinib (Inlyta) and pembrolizumab in April 2019 and followed by cabozantinib (Cabometyx) and nivolumab (Opdivo) in January 2021.2,3
All these combinations are approved for adult patients with advanced RCC in the frontline setting, regardless of their disease risk. This offers an advantage over previously approved IO/IO combinations, like nivolumab plus ipilimumab (Yervoy), which was approved in April 2018 for the treatment of patients with advanced RCC who presented with intermediate- or poor-risk disease.4
In a set of Case-Based Roundtable Meetings, Tian Zhang, MD, MHS, associate professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center in Dallas, and Randy F. Sweis, MD, assistant professor of medicine at the University of Chicago in Illinois, led discussions with fellow clinicians about ways they can approach treatment selection in this patient population using risk stratification and other baseline factors.
UNDERSTANDING RISK STRATIFICATION IN RCC
Zhang noted that per the National Comprehensive Cancer Network Clinical (NCCN) guidelines for treating patients with kidney cancer,5 therapeutic regimens are categorized based on their suitability for patients with favorable vs intermediate-/ poor-risk disease per either the International Metastatic RCC Database Consortium (IMDC) criteria or the Memorial Sloan Kettering Cancer Center prognostic model.
“NCCN guidelines for the treatment of advanced metastatic renal cell carcinoma were updated in 2023. You’ll note that treatments are denoted by IMDC criteria, which were initially brought out with VEGF therapies. And now, because it was used as a stratification marker in many of these registration trials for immunotherapy combinations, it’s a selection criteria for when we are thinking about immunotherapy combinations,” Zhang said.
Looking closely at preferred first-line therapy options for patients with clear cell disease, it is notable that 3 VEGF TKIs plus PD-1/PD-L1– targeting immune checkpoint inhibitor combinations carry category 1 recommendations for patients with both favorable- and intermediate-/poor-risk ccRCC: axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab. Additionally, preferred regimens for intermediate-/poor-risk ccRCC include nivolumab in combination with the CTLA-4 inhibitor ipilimumab with a category 1 recommendation and single-agent cabozantinib, which carries a category 2A recommendation.
For some, it may be difficult to justify using IMDC criteria when stratifying risk given that certain factors, such as a low Karnofsky Performance Status (< 80%) or platelet levels greater than the upper limit of normal (400-450 cells/μL), would automatically put otherwise low-risk patients into the intermediate-to high-risk group.
In discussing IMDC criteria for risk stratification, Sweis told his group: “[T]his historically had come from retrospective analyses showing…that more risk factors do [indicate] poorer prognosis.6 Now whether they’re causal or markers of aggressive disease biology is a different question that we don’t have answers to.”
Sweis explained IMDC criteria are more of a guidance for understanding the risk a patient’s disease might present, which may be evident without even looking at IMDC. “If a patient presents with a perfect performance status, zero symptoms, and a tiny lung nodule, they’re going to fall into the favorable-risk category anyway. And then conversely, the patients [with] lots of pain, spinal metastases, and rapid progression after surgery are going to be those who perform poorly.”
In cases such as the 2 described, Sweis said IMDC risk calculation may not be all that useful but that there are some subtle cases where it can be a helpful tool.
INFLUENCE OF DISEASE RISK ON OUTCOMES IN FIRST-LINE RCC
When selecting 1 of the 3 NCCN-recommended regimens for the treatment of first-line advanced ccRCC with favorable risk per IMDC, it’s important to understand the data from each of the clinical trials that led to and supported FDA approval.
The phase 3 KEYNOTE-426 trial (NCT02853331) of axitinib/pembrolizumab vs single-agent sunitinib (Sutent) met both of its primary end points of statistically significant OS (HR, 0.73; 95% CI, 0.60-0.88; P < .0001) and PFS (HR, 0.68; 95% CI, 0.58-0.80; P < .0001) improvement with the IO/TKI combination in the intent-to-treat (ITT) population.7 In the phase 3 CheckMate 9ER trial (NCT03141177) of cabozantinib/nivolumab vs sunitinib, the trial met its primary end point of superior PFS with the experimental regimen in the ITT population (HR, 0.59; 95% CI, 0.49-0.71; P < .0001), while also improving the secondary end point of OS (HR, 0.70; 95% CI, 0.56-0.87; P = .0014).8 Similarly, the phase 3 CLEAR trial (NCT02811861) showed that lenvatinib/ pembrolizumab resulted in statistically significant improvement in the primary end point of PFS vs sunitinib (HR, 0.47; 95% CI, 0.38-0.57; P < .0001); in this case, OS was also improved with active therapy (HR, 0.79; 95% CI, 0.63-0.99; P = .042).9
Sweis noted that although there were consistent, reliable, and similar improvements in OS and PFS with these regimens across the trial's ITT populations, looking at HRs for patients with favorable-risk disease paints a less clear picture regarding improvement with IO/TKI vs sunitinib alone. In all 3 pivotal trials, confidence intervals for the OS HRs cross or approach 1.00.
“Previously, discussion had been about what to do with the intermediate-/poor-risk disease, but treating favorable risk is a bit harder. [With these trials], we can line up the data and look at the OS HR in [patients with] favorable-risk disease and it’s not as robust as we see in the intention-to-treat population. It gets a little trickier in terms of comparison to TKI alone. There’s some thought that favorable-risk patients have different disease biology, and the disease tends to be more responsive to TKI than IO, so perhaps the combination has less benefit compared with sunitinib,” said Sweis.
However, data consistently show that these combinations result in improved response rates for patients in both the ITT and favorable-risk disease populations. “For both arms in each study, when you have a small volume of disease it’s potentially easier to get higher objective response rates [ORRs] in general as well higher complete response [CR] rates,” added Sweis.
ORRs in the ITT populations with experimental vs control therapy were consistently improved in the KEYNOTE-426, CheckMate 9ER, and CLEAR trials. And unlike outcomes of OS and PFS, ORRs and CR rates were also improved in patients with favorable-risk RCC treated with any of the 3 combinations (Table7-10).
Zhang agreed, stating, “For your patients who are shooting for complete responses, particularly with favorable-risk disease, you can potentially be picking any of the [frontline combinations] and expect 10% [or greater CR rates] from these immunotherapy-based combinations.”
Looking at rates of response, particularly achievement of CR, the data for the combination of lenvatinib plus pembrolizumab from the CLEAR trial are strong and may lead some to favor its use over the other available IO/TKI combinations, made evident by the highest rate of CRs across ITT and favorable-risk populations. Still, data continue to be updated and other factors may sway decision-making when choosing between these similar therapeutic regimens.
OTHER FACTORS FOR DECISION-MAKING
Survival and response outcomes are not the only considerations when choosing a therapy for patients in this space, particularly those who may be predisposed to certain adverse events (AEs).
“Discontinuation [rates] due to [AEs] are in the single digits for axitinib/pembrolizumab and cabozantinib/nivolumab combinations, but up to 13% for lenvatinib/pembrolizumab, perhaps due to the fact that lenvatinib is harder to tolerate,” explained Zhang.
Regarding AE management, Zhang noted that the short half-life of axitinib may help it edge out [in front of] other VEGF inhibitors because temporarily discontinuing administration of the drug for a mere 24 to 48 hours will help quickly determine whether AEs are from the immunotherapy or TKI.
“Axitinib has the shortest half-life of about 2 to 5 hours, so it really does wash out in less than 24 hours. Of the other TKIs, lenvatinib has [a half-life] of about 1 day or so,” Zhang said.
WHEN TO USE IO/IO
Zhang noted that the most recent data from the CheckMate 214 trial, which has the longest duration of follow-up of all the trials supporting combination regimens in frontline advanced RCC, showed that 30% of patients treated with nivolumab/ipilimumab did not progress at 5 years.10
“We have long-term follow-up for those patients, and durable responses are the ones that you are shooting for when you give ipilimumab/nivolumab. In kidney cancer, we’ve had multiple trials using salvage ipilimumab for patients progressing on nivolumab so there’s the caveat that if we don’t use CTLA-4 inhibition up front, we lose that effect for patients that have been exposed to PD-L1 inhibition,” Zhang said.
At the 2023 Genitourinary Cancers Symposium (ASCO GU), Michael Atkins, MD, deputy director of the Georgetown Lombardi Comprehensive Cancer Center and the Scholl Professor and vice chair of the Department of Medical Oncology at Georgetown University Medical Center in Washington, DC, and colleagues presented data from cohort A of the phase 2 HCRN GU16-260 trial (NCT03117309), which looked at nivolumab in patients with advanced ccRCC until progressive disease (PD), toxicity, or 96 weeks of treatment, followed by nivolumab/ipilimumab salvage therapy in patients with PD or stable disease at 48 weeks of treatment.
Of 128 patients treated, 28% went on to receive the salvage therapy. At the median follow-up of 37.7 months, treatment-free survival (TFS)—defined as time from protocol therapy cessation to subsequent therapy initiation or death—was high in patients with favorable-risk disease, leading investigators to conclude that nivolumab monotherapy with salvage dual immunotherapy (IO/IO) in nonresponders is a viable option in this patient population. The mean TFS in those with favorable- and intermediate-/poor-risk disease was 12.9 months (95% CI, 9.7-16.1) and 8.0 months (95% CI, 5.8-10.2), respectively.11
“It’s a somewhat controversial topic for favorable-risk disease. Atkins was grilled at ASCO GU this year because he took this approach of using ipilimumab plus nivolumab for favorable-risk disease. It’s potentially reasonable if you talk to the patient and they’re [concerned with] high chances for complete response and the toxicities of VEGF inhibitors. These may be reasons to try the IO/IO combination in this circumstance,” Zhang said.
BIOMARKERS AND GENOMIC DATA
Regarding genomic information, Zhang said there has been little data to justify selecting treatment based on these factors, but there may be opportunities to enroll certain patients in clinical trials if biomarkers are detected.
“In current practice, molecular results haven’t changed how you would manage [most patients], but the genomic data certainly are interesting. The samples I’ve sent [for next-generation sequencing (NGS)] haven’t yielded much that is actionable. However, there may be [the opportunity to enroll] a patient in a clinical trial,” Zhang said.
Sweis agreed that as far as NGS goes, there’s little known utility in the ccRCC space.
“[NGS is] something that we’re doing a bit more of in RCC. Traditionally, we haven’t done it much just because there have not been many actionable [targets]. It’s more helpful with non–clear cell RCC where you can sometimes find targetable mutations, like ALK.”
BRINGING DATA TOGETHER FOR DECISION-MAKING
Zhang and Sweis concluded their discussions by reviewing disease risk and other relevant factors that play into decision-making in advanced ccRCC therapy selection.
Zhang said some factors, like the presence of brain metastases that are not necessarily a part of typical patient risk assessment, would put patients into a poor-risk category as trials that have included cohorts of patients with these characteristics have shown poor outcomes.
Regarding higher discontinuation rates with lenvatinib vs pembrolizumab, Sweis said the trade-off may be worth it to some when considering the efficacy potential. “You [may be] getting better efficacy, or at least similar efficacy, in spite of more people coming off therapy.”
Both experts touched on the relevance of pharmaco-dynamic properties.
“There’s better VEGF selection with [third-generation] VEGF inhibitors like axitinib and more targets for the others, such as cabozantinib [with activity against] MET, AXL, FLT3, and RET and lenvatinib with FGFR and RET selection,” Zhang concluded.
According to Sweis, when considering which agents or regimens to favor, the pharmacodynamic properties of VEGF TKIs may play a bigger role when deciding what therapies to use after failure of a first-line regimen. “The efficacy data are similar [between regimens and] there are molecular differences that may allow us to get responses after 1 [previous TKI] fail,” he concluded.
1. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. August 10, 2021. Accessed August 1, 2023. https://tinyurl.com/ycyszrjv
2. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. April 19, 2019. Accessed August 1, 2023. https://tinyurl.com/y33dnzs8
3. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed August 1, 2023. https://tinyurl.com/bdzkxkj5
4. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed August 1, 2023. https://tinyurl.com/4ye3vae4
5. NCCN Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2024. Accessed August 1, 2023. https://tinyurl.com/h2y8hfef
6. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794-5799. doi:10.1200/JCO.2008.21.4809
7. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500
8. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603
9. Motzer RJ, Porta C, Eto M, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41(suppl 16):4502. doi:10.1200/JCO.2023.41.16_suppl.4502
10. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097. doi:10.1002/cncr.34180
11. Atkins MB, Jegede O, McDermott DF, et al. Treatment-free survival (TFS) outcomes from the phase II study of nivolumab and salvage nivolumab + ipilimumab in advanced clear cell renal cell carcinoma (aRCC) (HCRN GU16-260-Cohort A). J Clin Oncol. 2023;41(suppl 6):604. doi:10.1200/JCO.2023.41.6_suppl.604