Future direction of systemic therapy for advanced renal cell carcinoma: lessons from final and extended follow-up data from the CheckMate 9ER trial

The use of immune checkpoint inhibitors (ICIs) has significantly changed the treatment landscape of advanced renal cell carcinoma (RCC). Currently, dual ICI combinations (IO-IO; e.g., nivolumab plus ipilimumab) or combinations of ICIs with vascular endothelial growth factor receptors (VEGFR)-tyrosine kinase inhibitors (IO-TKI) are recommended as the standard of care for systemic therapy of previously untreated advanced RCC (1).

Motzer et al. recently reported extended follow-up data with median of 5.6 years from the randomized phase III CheckMate 9ER trial (2). This final protocol-prespecified analysis demonstrates the long-term efficacy and feasible toxicity profile of nivolumab plus cabozantinib over sunitinib in previously untreated advanced clear-cell RCC. Specifically, in intent-to-treat population, progression-free survival (PFS) favored nivolumab plus cabozantinib vs. sunitinib [median: 16.4 vs. 8.3 months, hazard ratio (HR): 0.58, 95% confidence interval (CI): 0.49–0.70]. Overall survival (OS) also favored nivolumab plus cabozantinib vs. sunitinib [median: 46.5 vs. 35.5 months, HR, 0.79 (95% CI: 0.65–0.96)]. The objective response rate (ORR) was higher with nivolumab plus cabozantinib than with sunitinib (55.7% vs. 27.4%). In all treated patients, any-grade and grade ≥3 treatment-related adverse events (AEs) occurred in 97.5% and 67.8% vs. 93.1% and 55.0% with nivolumab plus cabozantinib vs. sunitinib, respectively. No new deaths due to drug toxicity occurred since the previous reports. These results reaffirm the significance of nivolumab plus cabozantinib as a standard of care for patients with previously untreated advanced clear-cell RCC.

Similar to the CheckMate 9ER trial, extended follow-up data have been published in other pivotal clinical trials that have tested ICI combination therapy for advanced RCC (3-5). Increasing evidence regarding treatment outcomes has contributed to a more precise understanding of the long-term efficacy and safety profile of ICI combination therapy in advanced RCC. However, several medical needs in this field remain unmet. For example, it remains unknown which ICI combination regimens exhibit the best efficacy and tolerability in individual patients. This unanswered question is mainly due to the absence of head-to-head comparison trials using currently approved ICI combinations. To address this question, several network meta-analyses have been conducted using data from pivotal clinical trials. These indirect comparison analyses indicate that, at least in terms of PFS and ORR, IO-TKI, including nivolumab plus cabozantinib, exhibit superior therapeutic benefits over IO-IO (6-10). Conversely, data regarding OS remain conflicting; this may be due to the use of different follow-up data from clinical trials. When compared among IO-TKI combinations, an international multi-institutional retrospective and observational study recently indicated higher antitumor activity in terms of PFS and ORR with nivolumab plus cabozantinib than with pembrolizumab plus axitinib in a real-world population (11). Additionally, other real-world data indicated a comparable effectiveness profile between nivolumab plus cabozantinib and lenvatinib plus pembrolizumab, while the rate of grade ≥3 AEs was higher with lenvatinib plus pembrolizumab (12). These findings suggest that nivolumab plus cabozantinib is an effective treatment option for patients requiring tumor shrinkage due to disease-related symptoms or those planning to undergo nephrectomy or metastasectomy.

The present final report analyzed the predictive and prognostic effects of lung, bone, and liver metastases on PFS, OS, and ORR between nivolumab plus cabozantinib and sunitinib. This exploratory analysis showed that these three key outcomes were superior with nivolumab plus cabozantinib over sunitinib, demonstrating that this combination therapy is recommended as a standard treatment regardless of metastasis status. Cabozantinib has activity against several molecules, such as VEGFRs, mesenchymal-epithelial transition factor (MET), growth arrest-specific protein 6 (GAS6), and AXL receptor tyrosine kinase (AXL), and downregulates these mediators involved in carcinogenesis, proliferation, metastasis, angiogenesis, and maintenance of the tumor microenvironment (13). Notably, hepatocyte growth factor c-MET pathway has been shown to be particularly relevant in RCCs with bone metastases (14). Indeed, the previous randomized phase III METEOR trial demonstrated a feasible effect of cabozantinib over everolimus on PFS in patients with bone metastases, as well as a high tumor response in bone metastatic lesions (15). Thus, these findings indicate that nivolumab plus cabozantinib may be a preferred treatment option for this population. In contrast, lenvatinib plus pembrolizumab also demonstrated a survival benefit in patients with bone metastases, as reported in the CLEAR trial (16). Notably, an expert consensus study showed no clear indications for regimens in patients with bone metastasis (17). Collectively, the definitive therapeutic positioning of nivolumab plus cabozantinib among IO-TKI combinations warrants further exploration.

The present report further documented data regarding exploratory subgroup analyses of efficacy by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category (2). PFS, OS, and ORR were superior in the nivolumab plus cabozantinib arm than in the sunitinib arm in the intermediate- or poor-risk IMDC population, supporting the recommendation of nivolumab plus cabozantinib as a standard-of-care option for intermediate- and poor-risk patients. Although the prognostic role of the IMDC risk classification was established in the previous VEGFR-TKI era (18), it may remain effective in the current ICI era. A recent real-world study showed longer PFS and OS in patients treated with IO-TKI compared with those treated with IO-IO in the intermediate-risk populations, whereas survival outcomes were comparable between IO-TKI and IO-IO in the poor-risk populations (19), suggesting the potential role of outcome stratification in the IMDC risk classification. In the IMDC favorable-risk population, PFS and ORR were favored with nivolumab plus cabozantinib, whereas an OS benefit over sunitinib was not observed in the present final report. Notably, no difference in OS was found in the IMDC favorable-risk population in other clinical trials that tested ICI combinations (20). The pathogenesis underlying this finding remains unknown but may be potentially associated with the molecular subtyping of RCCs: RCCs categorized as IMDC favorable-risk, which are enriched in the angiogenic subtypes defined by genome-wide gene expression profiling, resulting in favorable angiogenesis-targeting drugs such as VEGFR-TKIs (21). Thus, the advantage of ICI combinations over VEGFR-TKIs can attenuate in the IMDC-favorable risk population. Interestingly, patients categorized into the very favorable-risk group, defined by the presence of three factors, namely Karnofsky Performance Status score >80, time from diagnosis to systemic treatment ≥3 years, and absence of brain, liver, or bone metastasis, showed further improved OS compared with those in the favorable-risk group (22,23). Collectively, these findings suggest that a therapeutic role for TKI monotherapy, rather than ICI combinations, may remain in such carefully selected populations (24).

Regarding safety, a network meta-analysis using the clinical trial data indicated that IO-TKI including nivolumab plus cabozantinib harbored a high risk of grade ≥3 AE development compared to IO-IO (6), while treatment discontinuation was more frequent in IO-IO compared to other regimens including nivolumab plus cabozantinib (8). A network meta-analysis study showed that nivolumab plus cabozantinib is associated with relatively higher risks of respiratory and blood-related AEs among ICI combinations (10). Thus, patients with underlying respiratory dysfunction (e.g., emphysema or smoking history) or anemia may not be optimal candidates for nivolumab plus cabozantinib. Appropriate management of AEs including immune-related AEs (i.e., irAEs) is essential to maintain treatment intensity and the patients’ quality-of-life (25). Notably, a subset of patients may achieve durable responses even after treatment discontinuation due to AEs during ICI treatment. An exploratory post hoc analysis from the CheckMate 214 trial demonstrated comparable OS with nivolumab plus ipilimumab between patients with and without irAEs as well as between those who discontinued treatment due to AEs and those who did not, indicating that all AEs did not negatively affect survival of ICI treatment (26). However, the prognostic role of AE development in ICI treatment remains under investigation (27), as it can also be affected by AE manifestation, grade, and treatment regimens (28). Regarding IO-TKI, some AEs appear to be overlapping, which complicates the identification of drugs requiring medication. A retrospective study showed that a reduced dose intensity of lenvatinib during the early treatment phase was associated with shorter PFS in patients treated with lenvatinib plus pembrolizumab for advanced endometrial cancer (29). Although the prognostic impact of TKI dose intensity in IO-TKI regimens for RCC remains unclear, excessive treatment withdrawal may decrease therapeutic efficacy. Therefore, further understanding of the mechanisms underlying AE development as well as the establishment of strategies for AE treatment and monitoring are required.

Strategy for subsequent systemic therapy following the failure of first-line therapy is also a topic of active discussion. The randomized phase III LITESPARK-005 trial demonstrated that belzutifan, a hypoxia-inducible factor 2α inhibitor, showed significant PFS and ORR benefits over everolimus in patients with clear-cell RCC who are previously treated with at least one ICI and VEGFR-TKI (30). Furthermore, the phase III LITESPARK-011 study is ongoing to investigate the efficacy and safety of a doublet treatment consisting of belzutifan and lenvatinib in patients with clear-cell RCC who received prior treatment with ICI and VEGFR-TKIs (31,32). Such advances in subsequent treatment strategies could potentially change the approach to the first-line therapy in some cases. Specifically, following nivolumab plus cabozantinib, no definitive indication exists on whether alternative TKI (e.g., axitinib) or belzutifan is a preferred option for second-line therapy. In the LITESPARK-005 trial, the majority of patients received belzutifan in the third line or later (30). Therefore, evidence supporting the use of belzutifan as second-line therapy after first-line ICI combinations remain limited. However, subgroup analysis from the LITESPARK-005 trial suggested relatively greater activity of belzutifan compared with everolimus when used as second-line therapy (30). Drug-induced toxicity is also a key determinant in selecting subsequent therapy. In patients who are intolerant to cabozantinib-induced toxicity, belzutifan rather than other TKIs may be an effective option, as it has a distinct mechanism of action (33). Taken together, these findings indicate that additional data regarding the treatment profile of second-line therapy including TKIs and belzutifan following nivolumab plus cabozantinib are required.

Finally, another unmet medical need for systemic therapy in advanced RCC is the absence of biomarkers for patient selection, which potentially limits the provision of the best treatment for individual patients. For instance, the predictive and prognostic roles of programmed death ligand-1 (PD-L1) expression and tumor mutation burden remain inconclusive (34,35). In addition, the prognostic significance of alterations in specific genes such as PBRM1 remains controversial (36-38). Profiling using clinical and gene expression data from the phase III IMmotion151 trial revealed that RCCs harbor several molecular subtypes. Notably, the molecular subtypes were significantly associated with the IMDC risk category and differential response to systemic therapy according to their class, namely ICIs or VEGFR-TKIs, targeting angiogenesis (21), indicating the role of molecular subtypes as predictive biomarkers. However, recent studies using data from another cohort of the phase III JAVELIN Renal 101 trial have highlighted that molecular subtyping alone does not clearly classify the treatment response to ICIs and VEGFR-TKIs (39). This finding suggests the difficulty of implementation as predictive biomarkers based on bulk transcriptome data alone in RCC. In this context, kidney injury molecule-1 (KIM-1) is gathering attention as a novel biomarker (40). Specifically, in a post-hoc analysis of CheckMate 214, high baseline KIM-1 levels were associated with worse clinical outcomes, including shorter OS. Furthermore, changes in KIM-1 levels from baseline to at 3-week were associated with PFS, OS, and ORR in patients treated with nivolumab plus ipilimumab but not in those treated with sunitinib (41). Another novel biomarker, soluble MAdCAM-1, has recently been identified. The relative overdominance of the genus Enterocloster induces the downregulation of MAdCAM-1 in high endothelial venules of the ileal lamina propria and mesenteric lymph nodes, leading to migration and tumor homing of enterotropic interleukin-17-producing immunosuppressive T cells, which express the α4β7 heterodimeric MAdCAM-1 receptor (42). Importantly, soluble MAdCAM-1 is shed into the blood with soluble MAdCAM-1 levels reflecting the ileal expression of MAdCAM-1. Remarkably, soluble MAdCAM-1 levels were positively associated with improved PFS and OS, independent of IMDC risk categories, based on independent trial cohorts (43). These findings highlight the need for biomarker-guided clinical trials to investigate microbiota-targeted interventions aimed at enhancing the efficacy of ICI-based treatments. Indeed, the efficacy and safety of gut microbiome-based treatment strategies, including supplementation with a bifidogenic live bacterial product (44) and fecal microbiota transplantation in the setting of ICI combinations, including nivolumab plus cabozantinib, for patients with RCC have been intensively investigated (45-47). However, the predictive and prognostic roles of such novel biomarkers remain to be fully validated. Further efforts are needed to advance precision medicine for ICI combination therapy in RCC (48).

In summary, the final and extended follow-up data from the CheckMate 9ER trial demonstrated sustained long-term efficacy and a manageable safety profile of nivolumab plus cabozantinib in patients with advanced clear-cell RCC. This suggests that the combination of nivolumab and cabozantinib is a feasible treatment option. However, there is still a need to establish a more effective and safe systemic therapy for RCC, including treatment selection for first-line and subsequent therapies, and to identify biomarkers that enable the realization of precision medicine to enhance the effectiveness and safety of ICI combinations. In addition, the definitive positioning of nivolumab plus cabozantinib among ICI combination therapies, particularly within IO-TKI regimens, under specific conditions such as IMDC risk, organ metastasis status, and other clinical factors (e.g., histology, presurgical treatment, or the presence of a sarcomatoid component) should be continuously evaluated to maximize its therapeutic benefit.

Acknowledgments

None.

Footnote

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