Overview and the IMDC Framework
The management of advanced and metastatic clear-cell renal cell carcinoma (ccRCC) has undergone a fundamental transformation, moving from single-agent tyrosine kinase inhibitor (TKI) therapy to combination regimens pairing immune checkpoint inhibitors (ICIs) with either TKIs (IO-TKI) or a second ICI (IO-IO). As of May 2026, treatment selection in both China and the United States is anchored to the International Metastatic RCC Database Consortium (IMDC) risk classification, which stratifies patients into favorable (0 factors), intermediate (1–2 factors), and poor risk (≥3 factors) based on six clinical parameters: Karnofsky performance status <80%, time from diagnosis to systemic therapy <1 year, hemoglobin below the lower limit of normal, hypercalcemia, neutrophilia, and thrombocytosis 1. Despite sharing this same stratification framework, China and the United States diverge significantly in which regimens are accessible, reimbursed, and guideline-preferred.
Risk-Stratified First-Line Standard of Care
Favorable-Risk Disease
For IMDC favorable-risk patients, TKI monotherapy remains an acceptable first-line option; however, multiple IO-TKI combinations are also guideline-recommended first-line treatments and are commonly used in clinical practice. Critically, updated long-term data from CheckMate 214 confirmed that nivolumab + ipilimumab did not demonstrate a meaningful OS benefit in favorable-risk patients (HR 0.80 at 9-year follow-up), making IO-IO therapy generally inadvisable in this subgroup 3. IO-TKI combinations show PFS benefit across risk strata but OS data in favorable-risk subgroups remain immature. Both the 2025 CSCO guidelines and current NCCN guidance acknowledge that single-agent TKI therapy or observation are defensible strategies for favorable-risk patients, and combination therapy is not mandated 13.
Intermediate and Poor-Risk Disease
Intermediate and poor-risk patients represent the primary target for IO-based combination therapy in both countries, though the available regimens differ substantially.
| IMDC Risk Group | US (NCCN 2025-2026) | China (CSCO 2025 / NMPA Status) |
|---|---|---|
| Favorable | Sunitinib or pazopanib monotherapy; IO-TKI optional | Sunitinib or pazopanib monotherapy; IO-TKI optional |
| Intermediate (1 factor) | IO-based combination therapy is generally preferred; selected patients may receive TKI monotherapy or active surveillance | IO-based combination therapy is generally preferred; treatment selection should consider access, reimbursement, and patient factors |
| Intermediate (2 factors) | IO-TKI or IO-IO combinations (Category 1) | IO-TKI preferred; pembrolizumab + axitinib or axitinib + toripalimab |
| Poor (≥3 factors) | IO-TKI or IO-IO combinations (Category 1) | IO-TKI preferred; axitinib + toripalimab increasingly used |
First-Line Regimen Comparison: Four Major Combinations
Pembrolizumab + Axitinib (KEYNOTE-426)
KEYNOTE-426 demonstrated OS HR 0.53 and ORR of 59.3% versus 35.7% for sunitinib across IMDC risk groups, with 5-year OS of 41.9% versus 37.1% and durable PFS (60-month PFS 18.3% vs. 7.3%) 13. Grade 3–5 adverse events occurred in 62.9% versus 58.1% for sunitinib, with a manageable profile. In the United States, this is an NCCN Category 1 regimen. In China, the combination received NMPA approval and is one of the preferred first-line options; however, NRDL reimbursement status as of May 2026 is not definitively confirmed, creating potential out-of-pocket burden 1.
Nivolumab + Cabozantinib (CheckMate 9ER)
CheckMate 9ER showed median PFS 16.6 versus 8.3 months (HR 0.58), OS HR 0.79, and ORR 55.7% versus 28.4%, with efficacy observed across IMDC risk groups, including favorable-risk patients 13. Grade 3/4 adverse events were reported in 68% of patients, driven by TKI-related toxicities including hypertension, diarrhea, and palmar-plantar erythrodysesthesia. In the United States, this is an NCCN Category 1 regimen usable across all risk groups. In China, while nivolumab is approved for other tumor types, cabozantinib does not carry an RCC-specific approval in the available regulatory data, making this combination inaccessible in routine Chinese practice outside of clinical trials 12.
Nivolumab + Ipilimumab (CheckMate 214)
At 9-year follow-up, the IO-IO dual checkpoint strategy showed ITT OS HR 0.71 with 108-month OS of 31% versus 20%, and sustained PFS probability of 23% versus 9% in intermediate/poor-risk patients 3. Grade 3–4 treatment-related adverse events were actually lower than sunitinib (46% vs. 63%), though discontinuation rates were higher (22% vs. 12%), reflecting the distinct immune-related adverse event (irAE) burden of dual-ICI therapy. In the United States, this regimen is an NCCN Category 1 option for intermediate and poor-risk patients and offers an important choice for those with contraindications to TKIs (e.g., severe hypertension, cardiac comorbidity). Retrospective data suggest that irAE development in IO-IO therapy is independently associated with longer PFS (HR 0.25) and OS (HR 0.42), a signal not observed with IO-TKI combinations, reflecting mechanistic differences 9. In China, dual-ICI is not recommended as a first-line standard by CSCO guidelines, partly due to toxicity management infrastructure demands and the availability of IO-TKI alternatives 1.
Lenvatinib + Pembrolizumab (CLEAR/KEYNOTE-581)
The CLEAR trial demonstrated the largest PFS effect size among first-line regimens (HR 0.39; median PFS 23.9 vs. 9.2 months), highest ORR at 71% (complete response 16.1% vs. 4.2%), and OS HR 0.79 13. However, grade ≥3 treatment-related adverse events reached 71.6%, the highest among the four regimens, with pembrolizumab discontinuation rates of 25%. This regimen is NCCN Category 1 in the US and is favored for patients with high tumor burden or aggressive disease biology. In China, lenvatinib lacks an RCC-specific regulatory approval in available datasets, restricting routine access to this regimen 12.
China's Domestic Alternative: Axitinib + Toripalimab
A critical development distinguishing the Chinese treatment landscape is the April 2025 NMPA approval of axitinib + toripalimab (RENOTORCH trial)—the first domestically developed IO-TKI combination for RCC—achieving ORR of 56.7% and median PFS of 18.0 months, comparable to imported IO-TKI benchmarks 1. This combination is positioned as a first-line standard for intermediate and poor-risk ccRCC, offering cost and access advantages over imported alternatives. An additional agent, anlotinib + bemcentinib (ETER100 trial), was expected to receive NMPA approval in 2025, further expanding China-specific options 1.
Post-Progression Sequencing
The negative CONTACT-03 trial is the cornerstone of modern sequencing guidance. In this phase 3 study of 522 patients, atezolizumab + cabozantinib failed to improve outcomes over cabozantinib monotherapy after prior ICI therapy (PFS HR 1.03; OS HR 0.94), while increasing serious adverse events (48% vs. 33%) 7. This finding definitively argues against sequential ICI re-exposure and has shaped current guidelines in both countries.
| Prior First-Line | Recommended Second-Line (US) | Recommended Second-Line (China) |
|---|---|---|
| IO-TKI combination | Cabozantinib (preferred); axitinib; tivozanib; belzutifan (post-IO + VEGF-TKI) | Axitinib; lenvatinib + everolimus; no continued IO therapy |
| IO-IO (dual ICI) | Cabozantinib (preferred); axitinib | Axitinib; lenvatinib + everolimus |
| TKI monotherapy | IO-TKI combination (pembrolizumab + axitinib; nivolumab + cabozantinib; lenvatinib + pembrolizumab) | Pembrolizumab + axitinib; axitinib + toripalimab |
The TIVO-3 trial confirmed tivozanib's activity in CPI-pretreated patients (median PFS 7.3 vs. 5.1 months vs. sorafenib; DOR 20.3 months in responders), supporting VEGF-TKI monotherapy as a rational post-ICI option 4. A systematic review of 48 publications (>4,900 patients total) confirmed anti-VEGF treatment activity across all regimens and prior CPI types, without new safety signals or increased irAE risk 6. In the United States, belzutifan (HIF-2α inhibitor, FDA-approved December 2023) offers a mechanistically distinct third-line option after both ICI and VEGF-TKI exposure; LITESPARK-005 demonstrated PFS HR 0.75 versus everolimus with improved tolerability 5. Belzutifan's approval and reimbursement status in China as of May 2026 were not confirmed in retrieved materials 5. The LITESPARK-011 trial is evaluating belzutifan + lenvatinib versus cabozantinib post-ICI, results pending 10.
Access, Approval, and Reimbursement
The United States offers the broadest access: all four major first-line combinations are FDA-approved and NCCN Category 1, with commercial insurance and Medicare/Medicaid typically providing coverage, though copay burden and prior authorization requirements vary 12. In China, the regulatory and reimbursement environment creates a fundamentally different clinical reality. Cabozantinib and lenvatinib lack confirmed RCC-specific NMPA approvals in available data, restricting nivolumab + cabozantinib and lenvatinib + pembrolizumab to clinical trials or off-label compassionate use 12. Pembrolizumab and nivolumab have multiple NMPA approvals in other tumor types (NSCLC, HCC, gastric, esophageal) but RCC-specific combination approvals remain limited or unconfirmed 2. Without NRDL coverage, patients may face monthly costs of 10,000–50,000 RMB ($1,400–$7,000 USD) for imported combinations. Access is further concentrated in major tertiary cancer centers, with rural hospitals frequently lacking both drug availability and toxicity management expertise 1.
Clinical Interpretation for Medical Professionals
No single regimen has demonstrated universal OS superiority across all IMDC risk groups, and real-world regimen selection must reconcile guideline recommendations with patient-level factors and local access realities. In the US, the choice among four guideline-concordant first-line options is guided by patient comorbidity (TKI contraindications favoring IO-IO), need for rapid tumor response (lenvatinib + pembrolizumab or nivolumab + cabozantinib for high ORR), and toxicity tolerance. In China, axitinib + toripalimab and pembrolizumab + axitinib are the practical pillars of first-line IO-TKI therapy, with TKI monotherapy retained as acceptable for selected intermediate-risk patients in cost-constrained settings.
Toxicity differences matter clinically: IO-IO regimens carry a unique irAE profile requiring corticosteroid management expertise, while IO-TKI combinations demand proactive management of hypertension, diarrhea, and hand-foot syndrome 39. Crucially, irAE development during IO-IO therapy may serve as a positive prognostic signal, while this association is absent in IO-TKI therapy—a mechanistic distinction relevant for patient counseling 9. Post-progression, routine ICI rechallenge is generally not recommended based on available evidence, including CONTACT-03, although selected investigational approaches remain under evaluation 7, and VEGF-TKI monotherapy or HIF-2α inhibition (where available) represent the evidence-based standard. Clinicians in China must account for the absence of cabozantinib and belzutifan in routine practice, relying on axitinib and lenvatinib + everolimus as second-line pillars. Across both healthcare systems, individualized treatment planning that integrates IMDC risk stratification, drug availability, reimbursement status, comorbidity profile, and patient preference remains the foundation of optimal ccRCC management in 2026.