With the advent of immune checkpoint inhibitors, advanced renal cell carcinoma (RCC) has gradually entered the “immunotherapy era.” Targeted therapy plus immunotherapy (IO+TKI) combinations are now recommended by major guidelines and have become part of the first-line treatment landscape for advanced RCC. Although head-to-head trials have unequivocally demonstrated the superiority of first-line IO+TKI combinations over TKI monotherapy, “superior” in the first line does not necessarily mean “optimal” across the entire treatment journey.The Dilemma of First-Line IO+TKI: No Standard Treatment After Progression
The major challenge with first-line IO+TKI therapy is the lack of a clearly established standard treatment after disease progression, particularly for Chinese patients. The CONTACT-03 and TiNivo-2 studies demonstrated that administering immunotherapy again after prior first-line immunotherapy does not provide a survival benefit.
The novel targeted agent belzutifan, either as monotherapy or in combination with lenvatinib, has improved progression-free survival (PFS) in patients previously treated with immunotherapy. However, because of its limited accessibility and indications, belzutifan is currently available primarily to patients with von Hippel–Lindau (VHL) disease-associated RCC who do not require immediate surgery.
From the perspective of comprehensive treatment management, first-line treatment decisions should not focus solely on immediate PFS. They should also consider how the initial regimen may “consume” or “preserve” subsequent treatment options.
Based on clinical investigations of different treatment strategies, “targeted therapy first, immunotherapy later” may be one potential approach to overcoming this dilemma.
Classical Targeted Therapy: A Cornerstone of Advanced RCC Treatment
Targeted therapy remains one of the standard first-line treatment approaches for advanced RCC.
The A6181034 study was a landmark trial that established sunitinib as a first-line standard. The study compared sunitinib with interferon-α as first-line treatment for advanced RCC. Median PFS (mPFS) with sunitinib reached 11 months, significantly longer than the 5 months observed with interferon-α.
In the Chinese phase IV study A6181132, first-line sunitinib achieved an mPFS of 61.7 weeks, equivalent to approximately 14.4 months.
The Efficacy of “Immunotherapy Later”: The Remarkable Second-Line PFS in FRUSICA-2
The FRUSICA-2 study compared the efficacy of fruquintinib plus sintilimab with axitinib or everolimus in patients with advanced RCC whose disease had progressed on, or who were intolerant to, first-line VEGFR-TKI therapy.
Results presented at ESMO 2025 showed that fruquintinib plus sintilimab achieved an mPFS of 22.21 months, significantly longer than the 6.90 months observed with axitinib or everolimus.
Based on these findings, in May 2026, the National Medical Products Administration (NMPA) approved fruquintinib plus sintilimab for patients with locally advanced or metastatic RCC who had previously received VEGFR-TKI therapy, experienced treatment failure, and had not received a PD-1 or PD-L1 inhibitor in the first line.
Treatment Sequencing: Is “Targeted Therapy First, Immunotherapy Later” Feasible?
“Immunotherapy First, Targeted Therapy Later” vs. “Targeted Therapy First, Immunotherapy Later”: Focusing on the First Line vs. Covering the Entire Treatment Journey
“Immunotherapy first, targeted therapy later” represents the current mainstream strategy. Patients receive an IO+TKI combination in the first line, followed by targeted therapy in the second line, either as single-target therapy or dual-target therapy. When appropriate, participation in clinical trials should be prioritized.
At present, NMPA-approved first-line IO+TKI regimens for advanced RCC include toripalimab plus axitinib and serplulimab plus anlotinib. According to the corresponding clinical studies, RENOTORCH and ETER100, first-line IO+TKI therapy achieved an mPFS of approximately 18.0–19.0 months. After failure of immunotherapy, second-line treatment with belzutifan achieved an mPFS of 5.6 months.
By contrast, “targeted therapy first, immunotherapy later” means initiating treatment with targeted therapy in the first line and reserving an IO+TKI combination for the second line. Taking sunitinib as an example, first-line targeted therapy achieved an mPFS of 14.4 months, while second-line IO+TKI therapy achieved an mPFS of 22.21 months.
When the two strategies are compared, the combined PFS1 + PFS2 appears longer with the “targeted therapy first, immunotherapy later” strategy than with “immunotherapy first, targeted therapy later.”
From the perspective of comprehensive treatment across multiple lines, therefore, “targeted therapy first, immunotherapy later” may be a more suitable strategy for selected patients with advanced RCC who are expected to receive multiple lines of therapy.
Safety Comparison Between the Two Treatment Sequences
Compared with “targeted therapy first, immunotherapy later,” the “immunotherapy first, targeted therapy later” strategy appears to be associated with higher rates of grade ≥3 treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and treatment discontinuation due to adverse events.
Among adverse events commonly reported across the respective studies, anemia and hypertension occurred more frequently with the “immunotherapy first, targeted therapy later” strategy.
Conclusion
Moving beyond the first-line mindset of “use the best drug first,” it is worth reconsidering how targeted therapy and IO+TKI therapy should be sequenced in advanced RCC.
Comprehensive management of advanced RCC should not be viewed as a battle in which everything is decided in the first round. Rather, it should be regarded as a carefully planned long-term campaign.
In clinical decision-making, the definition of “optimal” should not be limited to “choosing the best regimen.” It should be expanded to “designing the best treatment pathway.”
Although the “targeted therapy first, immunotherapy later” strategy still requires validation in prospective head-to-head studies, it provides an important potential approach for rethinking the comprehensive management of advanced RCC.
