CDK4 and CDK6 Inhibitors

CDK4 and CDK6 inhibitors block cyclin-dependent kinases 4 and 6, keeping the retinoblastoma protein unphosphorylated and arresting cells in G1 phase. They restore sensitivity to endocrine therapy and are used with an aromatase inhibitor or fulvestrant in hormone receptor-positive, HER2-negative breast cancer.

Classification. Palbociclib, ribociclib, abemaciclib.

Pharmacokinetics. All are metabolised by CYP3A4; steady state is reached within 8 days.

• Palbociclib 125 mg once daily for 21 days then 7 days off (28-day cycle); tablets can be taken with or without food, capsules with food.
• Ribociclib 600 mg once daily for 21 days then 7 days off (400 mg once daily in the adjuvant setting); with or without food.
• Abemaciclib 150 mg twice daily continuously (200 mg twice daily as monotherapy); adjuvant 150 mg twice daily for 2 years.
• Combined with letrozole 2.5 mg or anastrozole 1 mg daily, or fulvestrant 500 mg with ovarian suppression in premenopausal women.

Differences. Palbociclib and ribociclib cause neutropenia; ribociclib also prolongs the QT interval and raises liver enzymes; abemaciclib causes diarrhoea, venous thromboembolism and creatinine rise (blocks tubular secretion without reducing true clearance).

• First-line metastatic hormone receptor-positive disease: CDK4 and CDK6 inhibitor plus aromatase inhibitor.
• After endocrine progression: with fulvestrant.
• High-risk early disease: adjuvant abemaciclib (2 years) or ribociclib (3 years) with endocrine therapy.
• Neutropenia management: hold for grade 3 until neutrophils recover to 1.0 x 10^9/L or more, and restart at the same or reduced dose; reduce for febrile neutropenia.
• Dose reductions: palbociclib to 100 mg then 75 mg; ribociclib to 400 mg then 200 mg; abemaciclib to 100 mg then 50 mg twice daily.
• Diarrhoea with abemaciclib: start loperamide 4 mg at the first loose stool, then 2 mg after each loose stool (maximum 16 mg daily), with oral fluids.

Selection. Choose by toxicity profile: ribociclib in younger patients with good cardiac status; abemaciclib when neutropenia is a concern; avoid abemaciclib with a history of thromboembolism.

Contraindications. Pregnancy; QT prolongation or QT-prolonging drugs (ribociclib); severe liver impairment (ribociclib); concomitant tamoxifen with ribociclib; active serious infection.

Adverse effects. Neutropenia, leucopenia, anaemia, fatigue, nausea, stomatitis, alopecia, interstitial lung disease, hepatotoxicity, QT prolongation (ribociclib), diarrhoea and venous thromboembolism (abemaciclib).

Interactions. Avoid strong CYP3A4 inhibitors (ritonavir-boosted regimens, ketoconazole, clarithromycin; if unavoidable reduce palbociclib to 75 mg, ribociclib to 400 mg, abemaciclib to 100 mg twice daily); avoid strong inducers (rifampicin, phenytoin); grapefruit juice; QT-prolonging drugs.

Special groups.

• Pregnancy: contraindicated.
• Breastfeeding: avoid.
• Older adults: more neutropenia.
• Kidney impairment: abemaciclib creatinine rise is spurious; ribociclib 200 mg at creatinine clearance under 30 mL/min.
• Liver impairment: reduce palbociclib to 75 mg in severe; ribociclib 400 mg in moderate to severe; abemaciclib 100 mg twice daily in severe.

Monitoring. Full blood count on day 1 and day 15 of the first 2 cycles, then monthly; liver function every 2 weeks for the first 2 cycles with ribociclib; ECG before starting and on day 14 of cycle 1 and when clinically indicated (ribociclib); creatinine (cystatin C if needed) and bowel habit with abemaciclib.

Referral and escalation. Febrile neutropenia, QT over 480 ms, syncope, thromboembolism, new dyspnoea or cough, and grade 3 liver toxicity need urgent care.