Optimal choice of first-line treatment for advanced renal cell carcinoma based on the results of extended follow-up data

Immuno-oncology (IO) has been utilized in the treatment of renal cell carcinoma since the approval of nivolumab monotherapy as a second-line therapy. Results of randomized controlled trials involving untreated locally advanced and metastatic renal cell carcinoma patients have demonstrated efficacy, establishing IO-IO combinations and IO-TKI (tyrosine kinase inhibitor) combinations as standard treatments (1-5). Despite the expansion of treatment options, there are currently no biomarkers available for IO combination therapy, and the interpretation of existing data and toxicity profiles will be crucial determining factors. Figure 1 shows the overall survival (OS) and progression-free survival (PFS) for each drug over time, with the most recent data added (2-19).

Figure 1 HR for OS and PFS for each clinical trial over time. HR, hazard ratio; M, months of median follow-up; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival.

In the CheckMate 214 study (2), the IO-IO combination of ipilimumab and nivolumab demonstrated a significant prolongation in OS compared to the sunitinib group in the intention-to-treat (ITT) population [hazard ratio (HR): 0.68, 95% confidence interval (CI): 0.49–0.95]. Furthermore, when patients were stratified according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification (20), there was no significant OS prolongation in the Favorable risk group. However, the IMDC Intermediate/Poor risk group exhibited significant OS and PFS prolongation (OS: HR, 0.63, 95% CI: 0.44–0.89; PFS: HR, 0.82, 95% CI: 0.64–1.05). The combination of ipilimumab and nivolumab is characterized by a higher rate of progressive disease (PD) (17.6%) and a lower overall response rate (ORR) (39%) than IO-TKI (9). Nonetheless, it presents a more sustained response. In the ITT group, the PFS did not significantly differ from that of the sunitinib group. However, the Kaplan-Meier curve reached a plateau after 24 months, remaining at 30% for 60 months. Moreover, the OS consistently ranged between HR of 0.68–0.72 throughout the long-term course of the study, with no observed progression over time.

In the JAVELIN Renal 101 study (1), among the IO-TKI combinations, avelumab and axitinib demonstrated significant PFS (HR, 0.67, 95% CI: 0.57–0.79) compared to the sunitinib group in the ITT population. However, OS was not reached in the interim analysis, and follow-up was ongoing until the final analysis. In the recently published final analysis, OS was prolonged but not significantly different in the sunitinib group (OS: HR, 0.86, 95% CI: 0.70–01.06) (21). Other IO-TKI combinations, namely pembrolizumab and axitinib, nivolumab and cabozantinib, and pembrolizumab and lenvatinib, have already significantly prolonged OS compared to the sunitinib group in the ITT population. The respective trials reported the following results: KEYNOTE-426 (HR, 0.53, 95% CI: 0.38–0.74) (3), CheckMate9ER (HR, 0.60, 95% CI: 0.40–0.89) (4), and CLEAR (HR, 0.66, 95% CI: 0.49–0.88) (5). Notably, in the KEYNOTE-426 study, the OS HR values at 13, 31, 43, and 67 months were 0.53, 0.68, 0.73, and 0.84, respectively (3,11-13). Similarly, in the CheckMate9ER study, the OS HR values at 18, 24, 33, 44, and 56 months were 0.60, 0.66, 0.70, 0.70, and 0.77 (4,14-17), respectively, and in the CLEAR study, the OS HR values at 27, 34, and 50 months were 0.66, 0.72 and 0.79, respectively (5,18,19). OS HR values stratified into IMDC Intermediate/Poor risk group also increases over time. These results suggest a stable OS over long-term use of IO-IO combinations, as indicated by consistently favorable OS HR values. Conversely, IO-TKI combinations exhibited worsening OS HR values over time. However, despite this trend, significant OS prolongation was consistently observed with HR values in the latest analysis of each trial. In the decision-making process between IO-IO and IO-TKI, it is anticipated that IO-IO combinations will offer durable responses, albeit with inferior ORR and rates of PD compared to IO-TKI. Additionally, the lack of long-term data on IO-TKI has been a limitation until now. However, the 43-month data from the KEYNOTE-426 study (12) we are evaluating here showed maintenance of PFS, and similar results were reported with longer-term data of 5 years (13). This is the longest data of any IO-TKI, and the combination of pembrolizumab and axitinib is increasingly supported as a standard treatment option.

Another important aspect of treatment selection involves understanding adverse events (AEs). It is essential to note that direct comparisons between trials may not be appropriate due to differing patient backgrounds. Although less overall AEs were observed with IO-IO combinations compared to IO-TKI combinations, the rate of high-dose steroid use for immune-related adverse events (irAE) was 29% higher in IO-IO combinations compared to 11–27% in IO-TKI combinations (1,3,4,6).

Among IO-TKI combinations, pembrolizumab and lenvatinib had the highest incidence of Grade 3 or higher AEs (82.4%), whereas avelumab and axitinib had the lowest incidence (71.2%). When comparing AEs by category, the combination of nivolumab and cabozantinib was associated with higher rates of diarrhea (63.8%) and palmar-plantar erythrodysesthesia syndrome (40%), while pembrolizumab and lenvatinib showed higher rates of hypertension (52.3%), but lower rates of liver injury [aspartate aminotransferase (AST)/alanine aminotransferase (ALT): 9.4%/9.7%]. In contrast, the combination pembrolizumab and axitinib had higher rates of Grade 3 or higher AEs related to liver injury (AST/ALT: 6.8%/12.1%). Excluding serious irAE, it is important to determine the tolerability of AEs attributed to TKIs. Axitinib advantages over other TKIs are a potent vascular endothelial growth factor receptor (VEGFR) inhibition, little off VEGFR targeted effect (22). Furthermore, AEs related to axitinib are relatively manageable due to its short half-life among TKIs. Additionally, familiarity of clinicians with axitinib, because of its extensive use, is advantageous.

As outlined above, the consideration of IO-TKI combinations becomes pertinent when an early response is expected, and the selection should be driven by comprehensive data analysis, including the evaluation of AEs. The combination of pembrolizumab and axitinib has apparent strengths reaching the final analysis, and the ease of use associated with axitinib compared to other IO-TKIs enhances its appeal. As a standard treatment, the accumulation of real-world clinical data and the identification of biomarkers represent crucial future endeavors.

Acknowledgments

We would like to thank Editage (www.editage.jp) for English language editing.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-172/coif). The authors have no conflicts of interest to declare.

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