What are the dosing, safety monitoring, and management guidelines for tyrosine‑kinase inhibitors used in chronic myeloid leukemia, EGFR‑mutated non‑small‑cell lung cancer, metastatic renal cell carcinoma, gastrointestinal stromal tumour, and HER2‑positive breast cancer?

Tyrosine Kinase Inhibitors: Dosing, Safety Monitoring, and Management Guidelines

Chronic Myeloid Leukemia (CML)

First-line treatment options include imatinib 400 mg once daily, nilotinib 300 mg twice daily, or dasatinib 100 mg once daily, with selection based on cardiovascular risk factors and comorbidities rather than efficacy alone. 1

Standard Dosing by Agent

• Imatinib: 300-800 mg once daily depending on indication (CML vs GIST vs Ph+ ALL) 1
• Nilotinib: 300 mg twice daily for first-line; 400 mg twice daily for second-line therapy 1
• Dasatinib: 100 mg once daily for first-line; 70 mg twice daily or 140 mg once daily for second-line 1
• Bosutinib: 500 mg once daily for patients resistant or intolerant to prior therapy 1
• Ponatinib: 45 mg once daily for patients resistant or intolerant to prior TKI therapy 1

Response Monitoring Schedule

• Blood counts and differential: Every 15 days until complete hematologic response (CHR) achieved 1
• Bone marrow karyotype: At 3 and 6 months, then every 6 months until complete cytogenetic response (CCgR) achieved 1
• Quantitative RT-PCR (BCR-ABL%): Every 3 months until major molecular response achieved 1
• Mutational analysis: Only in case of failure or accelerated/blast phase 1

Response Definitions and Treatment Adjustments

• Optimal response at 3 months: BCR-ABL1 ≤10% and/or Ph+ ≤35% 1
• Optimal response at 6 months: BCR-ABL1 <1% and/or Ph+ 0 1
• Optimal response at 12 months: BCR-ABL1 ≤0.1% 1
• Failure criteria: Non-CHR or Ph+ >95% at 3 months; BCR-ABL1 >10% at 6 months; BCR-ABL1 >1% at 12 months 1

Second-Line Management

• After imatinib failure: Switch to nilotinib or dasatinib, considering BCR-ABL kinase domain mutations 1
• After nilotinib or dasatinib failure: Switch to the alternative agent or consider allogeneic stem cell transplant 1
• After failure of two or three TKIs: Consider allogeneic stem cell transplant 1

Critical Safety Monitoring

• Nilotinib: Requires baseline and periodic cardiovascular risk factor assessment due to arterial thrombosis risk 2
• Dasatinib: Monitor for bleeding complications due to platelet dysfunction; avoid NSAIDs 2
• QT prolongation monitoring: Required for nilotinib and dasatinib 1
• Hepatotoxicity monitoring: Required for lapatinib, pazopanib, ponatinib, regorafenib, and sunitinib 1

---

EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC)

EGFR mutation testing is mandatory for all patients with advanced non-squamous NSCLC before initiating first-line treatment, and erlotinib, gefitinib, or afatinib should be used as first-line therapy in mutation-positive patients. 3

Standard Dosing by Agent

• Erlotinib: 100-150 mg once daily 1
• Gefitinib: 250 mg once daily 1
• Afatinib: 40 mg once daily 1

Patient Selection and Testing

• Testing requirement: EGFR mutation testing using validated platforms in laboratories with external quality assurance 3
• Eligible histologies: Adenocarcinoma and adenosquamous carcinoma 3
• Performance status: Beneficial regardless of PS, including PS 3-4 patients who cannot tolerate chemotherapy 3

Treatment Sequencing

• If EGFR mutation discovered during chemotherapy: Interrupt or complete planned chemotherapy and switch to erlotinib 3
• Continuation beyond progression: May continue erlotinib beyond initial progression if patient lacks multiple systemic symptomatic lesions 3
• Expected response rate: 67% in patients with sensitizing mutations 3

Adverse Event Management

Cutaneous Toxicity

• Prophylaxis: Regular use of emollients to prevent rash, dry skin, and paronychia 1
• Grade 2 prolonged/intolerable toxicity: Dose reduction or interruption appropriate 1
• Treatment: Topical corticosteroids/antibiotics and oral antibiotics as indicated 1

Gastrointestinal Toxicity

• Diarrhea management: Low-fat, low-fiber diet; minimize fruit, red meat, alcohol, spicy food, and caffeine 1
• Diarrhea persisting >48 hours: Loperamide plus oral isotonic solution 1
• No improvement: Discontinue drug and restart with dose reduction when toxicity returns to Grade 1 or baseline 1

Resistance and Second-Line Options

• At progression: Test for EGFR T790M resistance mutation 3
• T790M-positive: Osimertinib is standard therapy if not previously received 3
• T790M-negative: Platinum-based chemotherapy is standard approach 3

Radiation Therapy Integration

• Oligometastatic disease (1-3 metastases): Consider radiation therapy after systemic erlotinib therapy 3
• Brain metastases (1-3 lesions): Stereotactic radiosurgery recommended 3
• Brain metastases (>3 lesions): Whole brain radiation therapy recommended 3
• Palliative indications: Bone metastases, chest wall pain, hemoptysis, airway obstruction 3

---

Metastatic Renal Cell Carcinoma (RCC)

Standard Dosing by Agent

• Axitinib: 5 mg twice daily 1
• Pazopanib: 800 mg once daily 1
• Sunitinib: 37.5-50 mg once daily (dosing depends on indication) 1
• Sorafenib: 37.5-50 mg once daily 1

First-Line Treatment Selection

• High or intermediate risk patients: Ipilimumab-nivolumab is preferred, but TKI (sunitinib or pazopanib) is alternative 1
• Hepatotoxicity monitoring: Required for pazopanib, sorafenib, and sunitinib 1

Target-Specific Considerations

• VEGFR-1, VEGFR-2, VEGFR-3 inhibition: Primary mechanism for axitinib, pazopanib, sorafenib, and sunitinib 1
• Multi-kinase inhibition: Sorafenib and sunitinib also target PDGFR, KIT, FLT3, CSF-1R, and RET 1

---

Gastrointestinal Stromal Tumor (GIST)

Standard Dosing

• Imatinib: 300-800 mg once daily for GIST indication 1
• Sunitinib: 37.5-50 mg once daily for GIST/RCC 1

Target Mechanisms

• Primary targets: KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-B 1
• Adjuvant post-operative setting: Continue TKI with monitoring via telemedicine 1

Monitoring Requirements

• No specific black box warnings for imatinib in GIST indication 1
• Hepatotoxicity monitoring: Required for sunitinib 1

---

HER2-Positive Breast Cancer

Standard Dosing

• Lapatinib: 1250-1500 mg once daily (dosing depends on indication) 1

Critical Safety Monitoring

• FDA black box warning: Hepatotoxicity 1
• Baseline and periodic liver function tests: Mandatory before and during treatment 1

Target Mechanisms

• Dual inhibition: EGFR and HER2 1
• Metabolism: Primarily via CYP3A4 and CYP3A5; also induces CYP3A 1

Metastatic Disease Management

• CDK4/6 inhibitors: Adapt doses or postpone to avoid neutropenia 1

---

Universal Drug-Drug Interaction Management

All TKIs except afatinib are primarily metabolized by CYP3A4, making drug-drug interactions a critical safety concern requiring systematic evaluation of all concomitant medications. 1

Strong CYP3A4 Inhibitors (Avoid or Adjust Dose)

• Ketoconazole effect: Increases imatinib AUC by 40% but bosutinib AUC by >8-fold 1
• Other strong inhibitors: Clarithromycin, itraconazole, ritonavir, voriconazole 1
• Clinical implication: Exposure increase varies widely between TKIs; bosutinib, lapatinib, and nilotinib show greatest increases 1

Strong CYP3A4 Inducers (Avoid)

• Rifampicin: Significantly reduces TKI exposure 1
• Other inducers: Phenytoin, carbamazepine, phenobarbital, St. John's wort 1

TKIs That Inhibit CYP Enzymes

• CYP3A4 inhibitors: Dasatinib, imatinib, nilotinib 1
• CYP2D6 inhibitor: Gefitinib 1
• CYP2B6 inhibitor: Crizotinib 1

TKIs That Induce CYP Enzymes

• CYP3A inducers: Crizotinib, lapatinib 1
• CYP1A2 inducers: Axitinib, erlotinib, pazopanib 1
• CYP1A1 inducer: Erlotinib 1

---

COVID-19 Pandemic Adaptations

Reduced Frequency Dosing

• Imatinib, nilotinib, dasatinib for CML: Continue treatment with monitoring via telemedicine 1
• EGFR TKIs for NSCLC: Continue treatment with monitoring via telemedicine 1
• GIST adjuvant TKIs: Continue with telemedicine monitoring 1

Immunotherapy Frequency Adjustments

• Nivolumab and pembrolizumab: Consider discontinuation after 2 years of treatment 1
• Durvalumab: Reduce frequency from Q3W to Q4W by increasing dose from 1200 mg to 1500 mg 1

---

Critical Pitfalls to Avoid

• Do not discontinue TKI therapy for minor adverse events: Dose modifications and supportive care should be attempted first, as maintaining optimal disease control is paramount for survival 1
• Do not use single-agent fluoropyrimidine when oxaliplatin-based regimens are indicated: This applies to high-risk stage II colon cancer, not TKI therapy 4
• Do not combine dasatinib with NSAIDs: Additive platelet dysfunction increases bleeding risk 2
• Do not ignore cardiovascular risk factors in nilotinib patients: Baseline and periodic assessment mandatory due to arterial thrombosis risk 2
• Do not assume all TKIs have equivalent drug-drug interaction profiles: CYP3A4 inhibitor effects vary 20-fold between agents (imatinib 40% vs bosutinib >800% AUC increase) 1
• Do not delay mutational analysis in CML treatment failure: BCR-ABL kinase domain mutations guide second-line TKI selection 1
• Do not use EGFR TKIs without confirmed EGFR mutation: Testing is mandatory before first-line treatment in advanced non-squamous NSCLC 3