A 62-year-old woman with metastatic renal cell carcinoma progresses on sunitinib after 8 months of treatment. She has good performance status and no significant comorbidities. What is the drug of choice for second-line therapy?

Explanation

## Second-Line Therapy After TKI Progression in RCC **Key Point:** Cabozantinib is the preferred second-line agent for metastatic renal cell carcinoma (mRCC) progressing on first-line VEGFR-TKI therapy (e.g., sunitinib), based on superior PFS and OS data from the METEOR trial (NCCN 2023–2024, ESMO, ASCO guidelines). ### Why Cabozantinib? Cabozantinib is a multi-kinase inhibitor targeting **VEGFR, MET, and AXL** — pathways implicated in resistance to sunitinib. The METEOR trial (Choueiri et al., NEJM 2015) demonstrated: - **Median PFS:** 7.4 months vs. 3.8 months (everolimus) — HR 0.58 - **Median OS:** 21.4 months vs. 16.5 months — HR 0.66 - Significant improvement in objective response rate (ORR: 21% vs. 5%) This OS benefit established cabozantinib as a **Category 1 preferred second-line option** in NCCN guidelines for patients progressing on prior anti-VEGF therapy. ### Comparison of Second-Line Options | Agent | Mechanism | Key Trial | Median PFS | Guideline Status | |-------|-----------|-----------|------------|-----------------| | **Cabozantinib** | VEGFR/MET/AXL TKI | METEOR | 7.4 months | **Preferred (Category 1)** | | **Nivolumab** | PD-1 checkpoint inhibitor | CheckMate 025 | 4.6 months | Preferred (Category 1) | | **Axitinib** | VEGFR-selective TKI | AXIS | 6.7 months | Acceptable alternative | | **Sorafenib** | VEGFR/BRAF/c-KIT TKI | Historical | 5.5 months | No longer preferred | ### Why Not the Other Options? - **Sorafenib (A):** Historically used post-sunitinib but now considered outdated; inferior PFS/OS compared to cabozantinib and nivolumab. Not a preferred agent per current NCCN/ESMO 2023–2024 guidelines. - **Nivolumab (B):** Also a Category 1 preferred option (CheckMate 025 showed OS benefit over everolimus), but cabozantinib is generally favored when prior immunotherapy has not been used and in patients with intermediate/poor risk features where TKI re-challenge is appropriate. - **Axitinib (D):** Acceptable second-line option (AXIS trial), but does not demonstrate OS benefit over comparators; less preferred than cabozantinib in current guidelines. **Clinical Pearl:** Per NCCN 2023–2024 and ESMO guidelines, **cabozantinib** and **nivolumab** are both Category 1 preferred second-line agents after VEGFR-TKI failure. Cabozantinib is particularly favored in patients with good performance status (as in this vignette) due to its dual PFS and OS benefit in the METEOR trial. ### Dosing - Cabozantinib: 60 mg orally once daily - Monitor for: hypertension, diarrhea, hand-foot syndrome, hepatotoxicity **Reference:** Choueiri TK et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. NEJM 2015; NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer, Version 2024.