This study provides the longest follow-up phase 3 data for first-line immunotherapy combined with targeted therapy in advanced renal cell carcinoma, demonstrating consistent benefits of avelumab plus axitinib in overall survival, progression-free survival, and objective response rate. Although statistical significance was not reached, the results suggest clinically meaningful advantages.
Literature Overview
The article ‘Final Analysis of the Phase 3 JAVELIN Renal 101 Trial of Avelumab Plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma’, published in ‘Annals of Oncology: Official Journal of the European Society for Medical Oncology’, reviews and summarizes the final analysis results of the JAVELIN Renal 101 trial, focusing on evaluating the efficacy and safety of avelumab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma (aRCC), particularly mature overall survival (OS) data. The study enrolled patients with previously untreated aRCC and compared OS, progression-free survival (PFS), objective response rate (ORR), and safety between the two groups in both the PD-L1–positive and overall populations. Results showed numerical advantages for the combination group in OS, PFS, and ORR, with particularly strong long-term efficacy and significantly longer duration of response than the control group, although the OS difference did not reach pre-specified statistical significance. This study provides important evidence for the long-term efficacy of immune checkpoint inhibitors combined with tyrosine kinase inhibitors in first-line aRCC treatment. The publication of this article marks a further consolidation of the clinical standing of this regimen based on mature real-world follow-up data.Background Knowledge
Advanced renal cell carcinoma (aRCC) is a highly vascularized and immunogenic tumor. Traditional targeted therapies have primarily relied on anti-angiogenic agents such as sunitinib, but their efficacy is limited and resistance is common. In recent years, immune checkpoint inhibitors (ICI) combined with tyrosine kinase inhibitors (TKI) have become the new standard of care for first-line treatment, as they can simultaneously activate anti-tumor immune responses and inhibit tumor angiogenesis, resulting in synergistic effects. PD-L1, or programmed death-ligand 1, is expressed in the tumor microenvironment and can suppress T-cell activity, making it a key target for ICIs. Avelumab is an anti–PD-L1 monoclonal antibody that blocks the interaction between PD-L1 and PD-1, thereby restoring T-cell function. Axitinib is a selective VEGFR inhibitor with anti-angiogenic properties. Previous phase 2 studies have indicated strong anti-tumor activity for this combination. JAVELIN Renal 101 was the first phase 3 randomized trial to report outcomes of this combination versus sunitinib, with earlier results showing significant improvements in PFS and ORR over sunitinib. However, OS, a key endpoint, was not mature at the time. Therefore, this final analysis provides the longest follow-up data to date, aiming to clarify whether the combination translates into a significant survival benefit. Current challenges include how to interpret the non-significant yet numerically favorable OS results, the potential influence of subsequent therapies due to crossover, and how to optimize patient selection. This study fills a critical gap in long-term follow-up data and provides a solid foundation for clinical decision-making and future trial design.
Research Methods and Experiments
This study was a global, multicenter, randomized, open-label phase 3 clinical trial (JAVELIN Renal 101, NCT02684006) that enrolled patients with previously untreated advanced clear cell renal cell carcinoma, regardless of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk stratification. Patients were randomized 1:1 to receive either avelumab plus axitinib or sunitinib until disease progression, unacceptable toxicity, or study withdrawal. The primary endpoints were independent blinded central review (BICR)–assessed progression-free survival (PFS) and overall survival (OS) in the PD-L1–positive population (≥1% immune cell expression). Secondary endpoints included OS, PFS, objective response rate (ORR), duration of response (DOR), safety, and patient-reported outcomes (PROs) in the overall population. All efficacy endpoints were assessed by both investigators and BICR. Safety was evaluated according to CTCAE v4.03 criteria. Survival data were estimated using the Kaplan–Meier method, and hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards models. The final analysis was conducted after long-term follow-up, with a minimum follow-up of 68 months, and data were cutoff on August 31, 2023.Key Conclusions and Perspectives
Research Significance and Prospects
This study represents the longest follow-up phase 3 trial of an ICI+TKI combination in aRCC to date, providing critical mature OS data. Although OS did not reach statistical significance, the combination therapy consistently demonstrated significant advantages in PFS, ORR, and DOR, supporting its long-term efficacy as a first-line treatment. The numerical OS benefit may have been influenced by subsequent therapies, particularly the high rate of crossover to ICIs in the control group, a common occurrence in the current treatment landscape of aRCC, suggesting that future OS analyses should account for crossover effects.
The results further solidify the role of avelumab+axitinib in first-line aRCC treatment, especially for patients seeking deep and durable responses. Long-term safety follow-up revealed no new signals, and patient-reported outcomes indicate no negative impact on quality of life, enhancing its clinical utility. Future research could explore biomarkers (e.g., IMDC risk, PD-L1 expression levels, genomic profiles) to optimize patient stratification and enable precision therapy. Additionally, head-to-head comparisons with other ICI+TKI regimens (e.g., pembrolizumab+axitinib) could help guide personalized treatment selection. This study also sets a benchmark for efficacy and safety for future combination strategies (e.g., dual immunotherapy, triplet regimens).
Conclusion
The final analysis of the JAVELIN Renal 101 trial provides the longest follow-up data to date comparing avelumab plus axitinib with sunitinib as first-line therapy for advanced renal cell carcinoma. Although the intergroup difference in overall survival (OS) did not reach pre-specified statistical significance, the combination therapy demonstrated clinically meaningful numerical improvements in median OS (44.8 vs 38.9 months), significantly prolonged progression-free survival, nearly doubled the objective response rate, and yielded more durable responses, with over 16% of patients maintaining response for up to 5 years. Long-term follow-up revealed no new safety signals, and patient-reported outcomes indicated no negative impact on quality of life. Given that over half of the patients in the sunitinib group subsequently received PD-1/PD-L1 inhibitors, which may have diluted the OS difference, these results still support the clinical value of the combination regimen. This study provides high-level, grade 1 evidence on the long-term efficacy and safety of immunotherapy combined with targeted therapy in aRCC, helping to guide clinical practice and future trial design, and underscores the importance of considering the impact of subsequent therapies when evaluating OS.
