Cabometyx (Cabozantinib) and Opdivo (Nivolumab) Treatment Regimen
Reading tools
In this article
1) What Is Cabozantinib + Nivolumab?
Cabozantinib (Cabometyx®)is an inhibitor of tyrosine kinases including vascular endothelial growth factor receptors (VEGFR), MET and AXL and is used as a targeted therapy (TKI). Nivolumab (Opdivo®) blocks the T-cell PD-1 checkpoint to strengthen antitumor immunity and is an immunotherapy. This dual regimen is a treatment option for advanced/metastatic renal cell carcinoma (RCC) in the first-line setting.
2) How Does It Work?
- Cabozantinib: Through VEGFR-2/3, MET, and AXL, it suppresses angiogenesis ; reduces immunosuppressive signaling in the tumor microenvironment; and impairs tumor-cell invasion/migration.
- Nivolumab: By blocking PD-1 on T cells, it releases the tumor’s ‘immune brake’ and increases antitumor T-cell activity in response.
- Rationale (Synergy): The TKI relaxes vascular and stromal barriers, facilitating immune access to the tumor; PD-1 blockade sustains T-cell effectiveness.
3) What Are the Treatment Goals?
- Extend progression-free survival (PFS) and improve overall survival (OS).
- Increase objective response rate (ORR) and achieve deeper, more durable responses.
- Rapidly control symptomatic disease burden (e.g., pain, hematuria).
- After systemic control in selected cases, prepare for local approaches (surgery, stereotactic radiotherapy).
4) Approved Indication and Clinical Position
- Indication: Advanced/metastatic RCCtreated with first-line cabozantinib + nivolumab.
- Risk group: All IMDC risk groups (favorable/intermediate/poor) are eligible.
- Biomarker: PD-L1 testing is not mandatory.
- Clinical position: Among evidence-based first-line options alongside other IO/TKI combinations (pembrolizumab+axitinib, lenvatinib+pembrolizumab) and IO/IO (nivolumab+ipilimumab); selection depends on comorbidities, toxicity profile, and patient preferencein each case.
5) Evidence Summary — Phase 3 CheckMate 9ER
Design: Open-label, randomized; first-line treatment in advanced/metastatic RCC. Comparison: Nivolumab (240 mg every 2 weeks) + cabozantinib (40 mg/day) vs sunitinib (50 mg, 4/2).
| Endpoint | Combination | Sunitinib | Statistics |
|---|---|---|---|
| PFS (BICR, median) | 16.6 months | 8.3 months | HR 0.51 (95% CI: 0.41–0.64) |
| OS | Superior (median not reached in most analyses) | — | HR ~0.60 (95% CI: ~0.40–0.89) |
| ORR | 55.7% | 27.1% | — |
6) Dosing and Administration Schedule
- Nivolumab (IV): 240 mg every 2 weeks or 480 mg every 4 weeks, infused over ~30 minutes.
- Cabozantinib (PO): 40 mg once daily, on an empty stomach (≥1 hour before or ≥2 hours after food). Swallow whole with water.
- Duration: Until disease progression or unacceptable toxicity.
- Missed dose: A missed cabozantinib dose may be taken if remembered the same day; skip it if the next dose is near. Do not take a double dose to compensate.
7) Administration and Cabozantinib Precautions
- Hypertension: Common; regular blood pressure monitoring at baseline and during treatment, with appropriate antihypertensive therapy, is required.
- Proteinuria and kidney function: Urine protein and creatinine should be monitored regularly.
- Hepatotoxicity: ALT/AST and bilirubin may increase; with concurrent nivolumab, consider immune hepatitis in the differential diagnosis.
- Hand–foot skin reaction (PPES): Moisturizing/keratolytic measures; according to grade, dose interruption/reduction.
- Bleeding, thrombosis, fistula, perforation, and wound healing: Rare but potentially serious with cabozantinib. Major surgery requires withholding for at least ~3 weeks beforehand; restarting is not recommended until wound healing.
- Nutrition: Grapefruit and Seville oranges should be avoided (CYP3A4-mediated interaction risk).
8) Pretreatment Checks and Monitoring Between Visits
- Baseline (≤14 days beforehand): ECOG, vital signs; COMPLETE blood count, biochemistry (ALT/AST, bilirubin, creatinine, electrolytes), TSH ± free T4, urine protein, blood pressure; hepatitis B/C and HIV serology recommended (immune hepatitis risk management).
- Imaging: At baseline, then every 8–12 weeks (more often if clinically needed).
- Between visits: During the first 2–3 months, every 2–4 weeks, laboratory and BP checks; intervals may increase once stable. Home BP monitoring is useful.
- Symptom education: Warning signs such as diarrhea, rash, breathlessness, jaundice, abdominal pain, or severe fatigue require early medical contact.
9) Patient Selection Criteria
- IMDC risk: Suitable in favorable/intermediate/poor-risk groups.
- Autoimmune disease/organ transplantation: Active/severe autoimmunity and a history of solid organ transplantation may make IO contraindicated or high-risk ; careful assessment is required.
- Uncontrolled hypertension, serious bleeding risk, recent major surgery: For cabozantinib, a relative contraindication or treatment delay may apply.
- Hepatic/renal impairment: Dose adjustments and closer monitoring may be necessary.
10) Drug Interactions
- Cabozantinib – CYP3A4 substrate:
- Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, etc.) increase exposure → consider dose reduction (e.g., 40→20 mg).
- Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St. John’s wort) reduce exposure → where possible, avoid them; if no alternative exists, monitor closely and adjust according to protocol.
- Food–drug: Grapefruit/Seville oranges should be avoided. Cabozantinib must be taken on an empty stomach as directed.
- Nivolumab: No conventional CYP interactions; immunosuppressants (high-dose steroids, etc.) may reduce efficacy (except when treating immune-related AEs).
11) Side Effects and Management
| Side effect | Source | Management (summary) |
|---|---|---|
| Hypertension | Cabozantinib | Antihypertensives; temporary withholding/reduction at grade ≥3. |
| PPES (hand–foot) | Cabozantinib | Skin care, topical treatment; grade-based dose modification. |
| Diarrhea/stomatitis | Both (more often TKI) | Supportive care; withhold/reduce cabozantinib if severe; steroids for suspected immune colitis. |
| Hepatotoxicity | Both | Enzymes ↑: reduce dose if TKI-related; steroids ± withholding for immune hepatitis. |
| Pneumonitis | Nivolumab | Withhold + steroids at grade 2; permanently discontinue at grade 3–4. |
| Endocrinopathy (hypo/hyperthyroidism, hypophysitis) | Nivolumab | Hormone replacement; short-term steroids in moderate-to-severe cases. |
| Bleeding/fistula/perforation | Cabozantinib | Urgent assessment; permanent discontinuation if necessary. |
12) Dose Modifications
Typical cabozantinib steps
- Starting dose: 40 mg once daily.
- 1st reduction: 20 mg once daily.
- 2nd reduction: 20 mg every other day or longer intervals according to clinical protocol.
- Stop–restart: For grade ≥3 toxicity or persistent grade 2 events, temporarily withhold; once improved, restart at a lower dose.
Approach to Nivolumab Immune-Related AEs
- Grade 2: Temporarily withhold according to the affected organ; prednisone equivalent ~0.5–1 mg/kg/day; restart after improvement.
- Grade 3–4: For most organs, permanently discontinue + high-dose steroids (1–2 mg/kg/day) with tapering; if refractory, consider second-line immunosuppression (e.g., infliximab, mycophenolate).
- Exceptions: Endocrinopathies can generally be managed with hormone replacement while continuing treatment (clinical judgment is essential).
SGK Reimbursement Status
-
Opdivo with cabozantinib is on the list of drugs usable without additional TİCK approval for first-line treatment of adults with advanced clear-cell renal carcinoma, Karnofsky performance score 70 or above, and no active brain metastases. However, nivolumab is not reimbursed by SGK for this indication.
- For cabozantinib:
SGK reimburses first-line monotherapy until progression in intermediate- or high-risk metastatic clear-cell renal cancer. It also reimburses treatment until progression in metastatic clear-cell renal cancer progressing after at least one line of Vascular Endothelial Growth Factor (VEGF)-targeted therapy and/or one line of anti-PD-1 monoclonal antibody therapy. After progression on cabozantinib, sequential or combined temsirolimus, sunitinib, sorafenib, or pazopanib is not reimbursed.
- Price:
- Cabometyx 20, 40 and 60 mg tablets: 157,985.37 TL.
- Opdivo 100 mg vial: 38,053.16 TL, and Opdivo 40 mg vial: 15,221.26 TL.
13) Sources
- Choueiri TK, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced RCC. NEJM. 2021;384:829–841. (CheckMate 9ER). PubMed
- US FDA. FDA approves nivolumab + cabozantinib for previously untreated advanced RCC (2021). Link
- OPDIVO® (nivolumab) Prescribing Information (US). PDF
- CABOMETYX® (cabozantinib) Prescribing Information (US). PDF
- EMA. Cabometyx — Product Information (EU). PDF
- ESMO Guidelines Committee. Renal cell carcinoma: ESMO Clinical Practice Guidelines. (Current edition). ESMO
- NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer (current version). NCCN
Was this article helpful?
Your feedback helps us improve our content.
Reader comments
Share your comment
Your name and comment are published only after administrator approval. Your email address is never shown to visitors.
Be the first to comment.