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Advances in Therapeutic Strategies for Advanced Renal Cell Carcinoma: A Comprehensive Review

Advanced renal cell carcinoma (RCC) accounts for about 2% of cancer deaths globally, and its incidence is increasing in the United States and worldwide.1 Clear cell RCC (ccRCC) comprises about 75% of RCCs and is the most aggressive subtype, although survival rates are substantially improving with the advent of targeted systemic therapies and immune checkpoint inhibitors. In this editorial, I update readers on current therapeutic approaches for patients with advanced RCC, including clear cell and other histotypes. I also review the role of (neo)adjuvant treatment and biomarkers in advanced RCC management.

First-line treatment of advanced, unresectable ccRCC

As recently as 2017, the recommended first-line systemic treatment for advanced, unresectable ccRCC was monotherapy with an anti-angiogenic agent, such as the multi-target tyrosine kinase inhibitor (TKI) sunitinib.2 Since then, several dual-agent combinations have outperformed sunitinib in large phase 3 trials and are now recommended by major professional societies.3,4 Combining systemic therapies with distinct mechanisms of action is one strategy to improve the probability of treatment response and its speed, depth, and duration. Currently recommended combinations include the anti-PD-1 checkpoint inhibitor pembrolizumab plus the TKI axitinib (KEYNOTE-4265), pembrolizumab plus the TKI lenvatinib (CLEAR6), the anti-PD-1 checkpoint inhibitor nivolumab plus the TKI cabozantinib (CheckMate 9ER7), and dual-immune checkpoint inhibitor therapy with the CTLA-4 inhibitor ipilimumab plus nivolumab (CheckMate 2148).

At recent meetings, researchers have reported favorable updates from these trials. At ASCO GU 2024, KEYNOTE-426 investigators reported that after 5 years of follow-up, pembrolizumab/axitinib continued to show significant benefits in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared with sunitinib.9 At the same meeting, CheckMate 9ER researchers reported that after extended (median 55.6-month) follow-up, nivolumab/cabozantinib continued to demonstrate meaningful long-term efficacy benefits compared with sunitinib with respect to OS, PFS, and health-related quality of life (HRQoL).10 Additionally, at ASCO 2023, we learned that in the CLEAR trial, lenvatinib/pembrolizumab continued to produce significant improvements in PFS on next line of therapy (PFS2), HRQoL, and OS, when compared with sunitinib in a final prespecified analysis that included an additional 23 months of follow-up after primary data cutoff.11

Currently, ongoing trials are evaluating novel combination regimens as first-line systemic therapies for advanced ccRCC. The phase 3 LITESPARK-012 trial compares pembrolizumab plus lenvatinib, with or without belzutifan (a novel hypoxia-inducible factor-2 alpha [HIF-2α] inhibitor) or quavonlimab (an anti-CTLA-4 antibody) in approximately 1,600 patients with advanced ccRCC.12 Primary completion of this study is expected in 2026. Note that with all immune oncology (IO)-based regimens, patients should be educated about and monitored for immune-related adverse events, and clinicians should lean toward early treatment interruption and referral to specialized care if an event is significant (defined as grade 3 or above) or is worsening.

Risk stratification

Risk stratification in RCC helps guide treatment selection. It is based on clinical and laboratory parameters such as time since diagnosis, Karnofsky performance status, and the results of standard blood tests (LDH, calcium, and hemoglobin when using the Memorial Sloan Kettering Cancer Center [MSKCC] Prognostic Model, and hemoglobin, calcium, neutrophil, and platelet concentrations when using International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk criteria).3 Favorable-risk groups have none of these risk factors, while intermediate-risk groups have 1-2 factors and poor-risk groups have 3 or more. Ipilimumab/nivolumab, the first of the dual-agent systemic combinations to receive FDA approval in ccRCC, has the longest follow-up (more than 8 years in Checkmate 214)13 and is specifically recommended for treating poor/intermediate-risk RCC.3,4 The other three combinations are recommended in both favorable and poor/unfavorable ccRCC risk settings.

Biomarkers

With several treatment options now available in advanced RCC, predictive biomarkers are urgently needed to optimize treatment selection. Following the development of next-generation sequencing technologies, several gene expression signatures have emerged that may help select among immuno-oncologics (IOs) and anti-angiogenic therapies.14 The phase 2 BIONIKK study was one of the first prospective, biomarker-driven randomized trials in advanced ccRCC.15 In this study, a 35-gene expression signature assay that identifies ccRCC subgroups with different tumor microenvironments and TKI sensitivities was used to molecularly select patients for first-line treatment with sunitinib, nivolumab, or nivolumab plus ipilimumab. Although the study demonstrated promising ORR and PFS results, biomarker-based approaches will require validation in studies such as OPTIC (NCT05361720; currently recruiting) and others. OPTIC assesses the utility of RNA-seq based biomarkers to select patients for treatment based on biologic drivers relevant to angiogenesis (nivolumab/cabozantinib) and the immune microenvironment (ipilimumab/nivolumab).

Second and later-line systemic therapy for advanced ccRCC

Recommended options in this setting include TKIs, IOs, and IO-TKI combinations. Studies have shown that TKIs have activity in post-IO settings.16,17 In the randomized, controlled, dual-arm, phase 3, TIVO-3 study, third or later-line monotherapy with the TKI tivozanib was better tolerated than sorafenib and significantly improved PFS at initial and subsequent (3 and 4-year) follow-up.18,19 These findings paved the way for the FDA approval of tivozanib in 2021 for treating advanced RCC in patients who have already received at least two lines of therapy.

Previously, a phase 1b/2 study of pembrolizumab plus lenvatinib demonstrated an ORR of more than 55% among patients whose ccRCC had progressed on prior IO therapy.20 However, the phase 3 CONTACT-03 trial showed that adding atezolizumab to cabozantinib was not superior to cabozantinib alone for patients with advanced RCC that was treatment refractory (i.e., had progressed on PD[L]-1 inhibitors within 6 months).21 Thus, we currently lack clear evidence to support salvage IO therapy in patients who have progressed on IO therapy. A second phase 3 trial, TiNivo-2, will help clarify this question by evaluating whether adding nivolumab to tivozanib further improves PFS in patients with pre-treated RCC; primary PFS results are expected this year.22

Most recently, in December 2023, the HIF-2α inhibitor belzutifan received FDA approval for treating advanced RCC following a PD-1/L1 inhibitor and a VEGF-TKI. The approval was based on results from the phase 3 LITESPARK-005 trial, which compared belzutifan with everolimus (an mTOR inhibitor that is FDA-approved for treating advanced RCC after failure of sunitinib or sorafenib) in patients with sporadic, advanced RCC that had progressed following anti-PD-1/L1 and VEGF-TKI treatment. Primary results were reported at ESMO 2023, while patient-reported outcomes were reported at ASCO GU 2024. The investigators reported that belzutifan was associated with superior PFS and ORR, improved disease-specific symptoms and quality of life, and longer time to confirmed deterioration when compared with everolimus.23,24

Adjuvant Therapies for ccRCC

A significant proportion of patients presumed to have localized RCC have their disease recur after surgery, making adjuvant therapy an important consideration, especially in high-risk disease. The first class of drugs evaluated for adjuvant therapy in RCC were the anti-angiogenics, including sunitinib, sorafenib, pazopanib, and axitinib. Results have been underwhelming: Adjuvant sorafenib, pazopanib, and axitinib all failed to meet primary endpoints in separate trials,25 leaving sunitinib as the only TKI to receive an FDA approval for adjuvant use in RCC. The approval was based on the phase 3 S-TRAC trial, in which disease-free survival (DFS) was significantly greater with sunitinib compared with placebo after nephrectomy in patients with locoregional ccRCC at high risk for recurrence.26 Importantly, toxicities, including grade 3 and 4 events, were approximately three times more frequent in the sunitinib arm versus the placebo arm and frequently led to dose reductions and/or dose interruptions. Furthermore, in an updated analysis of S-TRAC trial data, median OS was not reached in either arm after more than 6.5 years’ median follow-up.27

Other targeted therapies have been investigated in the adjuvant RCC setting, most notably everolimus. Recently, in the phase 3 randomized placebo-controlled EVEREST trial, everolimus missed its statistical cutoff for improving relapse-free survival (RFS) in patients with intermediate-risk or high-risk RCC.28 However, a subgroup analysis of very high-risk patients revealed a statistically significant 21% improvement in RFS with everolimus. Treatment discontinuation was a factor in this trial—adverse events included oral mucositis, which can be particularly hard for some patients to tolerate. The benefit seen in the high-risk population might justify further investigation of everolimus in the adjuvant setting; biomarker analysis will be very important to guide decisions about the use of this therapy.

Among the IO therapies, pembrolizumab is currently the only one to have received FDA approval (in November 2021) for adjuvant use in RCC. This approval was based on positive results from the randomized phase 3 placebo-controlled KEYNOTE 564 study, in which adjuvant pembrolizumab therapy significantly improved DFS among patients with RCC at intermediate-high or high risk of recurrence after nephrectomy.29 Remarkably, adjuvant pembrolizumab therapy also significantly improved OS when compared with placebo, as we learned at ASCO GU in January 2024.30 Other IOs did not demonstrate similar benefits in their respective phase 3 trials, including PROSPER, IMmotion010 and CheckMate 914.25

A few trials are testing other combinations, such as RAMPART, which compares adjuvant durvalumab, adjuvant durvalumab/tremelimumab, or active monitoring in patients with resected primary RCC at high or intermediate risk of relapse; results are expected later this year.31 In addition, the phase 3 LITESPARK-022 (MK-6482-022) trial compares adjuvant pembrolizumab plus belzutifan with adjuvant pembrolizumab alone; results are expected in 2027.32 Other studies are being designed.

Neoadjuvant therapy

Neoadjuvant therapy aims to eliminate micrometastatic disease and improve tumor resectability prior to surgery, thereby decreasing perioperative complications and risk of recurrence. This approach is not a standard of care in RCC, but it remains an area of study. The single-arm phase 2 NeoAvAx trial was the first neoadjuvant study to combine an IO (avelumab) with a TKI (axitinib).33 At ASCO GU 2022, study investigators reported a 30% rate of partial response, indicating some antitumor activity with this combination.33 Median primary tumor downsizing was 20%, and 10 of 12 responders remained disease-free after a median follow-up time of 23.5 months. PROSPER, the first phase 3 neoadjuvant study in RCC, failed to show an improvement in RFS with perioperative nivolumab versus surgery alone in patients at high risk for recurrence; OS data were immature at last report, but showed no significant difference between arms.34 More neoadjuvant studies of IO therapies are recruiting or planned.

Non-clear cell RCC (nccRCC)

Non-clear cell histologic subtypes comprise about 20%-25% of RCC cases.1 These include papillary RCC (the most common non-clear cell histotype), TFE3-translocation RCC, fumarate hydratase and succinate dehydrogenase-deficient RCC, chromophobe RCC, collecting duct RCC, and medullary RCC. For patients with localized nccRCC, postsurgical prognosis varies by histology. In a large observational study, patients with sarcomatoid or collecting duct RCC had a 5-year OS of less than 45%, far lower than among patients with papillary and chromophobe subtypes.35

Conventionally, nccRCC has been treated with the same therapies as those used in ccRCC, but response rates are often lower, and advanced nccRCC often is associated with a poor prognosis, making clinical trial participation a priority.36 Prior phase 2 studies of advanced nccRCC, including ESPN,37 ASPEN,38 and RECORD-3,39 supported the upfront use of sunitinib over everolimus. Subsequently, in the randomized, open-label, phase 2 SWOG 1500 trial of patients with untreated or previously treated advanced papillary RCC, cabozantinib was associated with superior PFS compared with sunitinib.40 Of note, neither the TKI crizotinib nor the MET inhibitor savolitinib demonstrated a PFS benefit compared with sunitinib.

In nccRCC, as in ccRCC, combination regimens are increasingly being used to treat patients with advanced disease. In a phase 2 study, combination cabozantinib/nivolumab therapy achieved promising responses in papillary RCC but showed limited or absent responses in chromophobe RCC, although this latter cohort was small (7 patients) and included relatively few progressors.41 Another combination regimen, lenvatinib/pembrolizumab, also has shown activity in variant RCC subtypes, including a confirmed ORR of 49% in the phase 2 KEYNOTE-B61 trial.42 Novel therapies are also being investigated in nccRCC, such as zanzalintinib, a novel next-generation oral TKI. After posting promising results across a range of tumors in a phase 1 trial,43 zanzalintinib is being investigated in the multicenter phase 3 STELLAR-304 study, which compares the combination of zanzalintinib/nivolumab with sunitinib.44

Summary

Optimizing treatment selection throughout the RCC disease course can improve clinical outcomes, quality of life, and cost-efficacy. Combination regimens with TKIs and IOs are now the standard first-line treatment for advanced/metastatic ccRCC, having demonstrated a clear benefit over TKI monotherapy in randomized phase 3 trials. In the recurrent/treatment-refractory setting, the novel HIF-2α inhibitor belzutifan received FDA approval in December 2023 for treating patients whose advanced RCC has recurred after a PD-1/L1 inhibitor and a VEGF-TKI. We continue to see a transition toward the use of IOs earlier in the disease course, with the aim of potentially improving patient outcomes and preventing or postponing metastatic disease. This shift will have implications for treatment sequencing and affect decisions about later-line therapy. Research on biomarkers continues and will be vital for treatment selection as more therapeutic combinations become available. Given the high rate of recurrence of presumed localized RCC after surgery, research into adjuvant and neoadjuvant therapies remains vital; currently, adjuvant pembrolizumab is approved and has been shown to improve OS in intermediate and high-risk RCC. Research into non-clear cell histologies is increasing, although a gap in knowledge persists.

Written by: Pedro C. Barata, MD, MSc, Associate Professor of Medicine at Case Western University and the Director of Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland, Ohio. 

References:

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  44. Pal SK, Powles TB, Kanesvaran R, et al. 1912TiP STELLAR-304: A randomized phase III study of zanzalintinib (XL092) and nivolumab in non-clear cell renal cell carcinoma (nccRCC). Annals of Oncology. 2023;34:S1028-S1029.