What is the classification, mechanism of action, and side effects of Geftinib (Iressa)?

Gefitinib: Classification, Mechanism of Action, and Side Effects

Classification

Gefitinib is a first-generation, reversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for first-line treatment of metastatic non-small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. 1

• Gefitinib is specifically indicated for patients with activating EGFR mutations (particularly exon 19 deletions and L858R mutations) regardless of performance status 1
• It is classified as a Category 1 (highest level) first-line therapy option for EGFR mutation-positive advanced NSCLC 1
• Unlike second-generation TKIs (afatinib) which irreversibly bind EGFR, gefitinib is a reversible inhibitor 2
• Unlike third-generation TKIs (osimertinib) which target T790M resistance mutations, gefitinib does not effectively inhibit this resistance mechanism 2

Mechanism of Action

Gefitinib selectively inhibits the EGFR tyrosine kinase domain by competitively binding to the ATP-binding site, thereby blocking downstream signaling pathways critical for cancer cell survival and proliferation. 3, 4

Molecular Mechanism:

• Gefitinib dose-dependently inhibits EGFR autophosphorylation and downstream intracellular signaling 3
• In EGFR-mutant NSCLC cells, gefitinib specifically blocks Akt and STAT survival pathways that are preferentially activated by mutant EGFR, leading to extensive apoptosis 4
• Mutant EGFR proteins selectively transduce survival signals rather than proliferation signals (ERK pathway), making these cells particularly dependent on EGFR signaling and thus highly sensitive to gefitinib 4
• Gefitinib is orally bioavailable and cleared via the cytochrome P450 3A4 pathway, reaching steady-state plasma concentrations in 7-10 days 3

Clinical Efficacy:

• In EGFR mutation-positive patients, gefitinib demonstrates objective response rates of 71% compared to 47% with chemotherapy 1
• Median progression-free survival ranges from 9.7 to 24.9 months in mutation-positive patients 1
• Critical caveat: Gefitinib is harmful in EGFR mutation-negative patients, with significantly worse outcomes (HR 2.85) compared to chemotherapy, making mutation testing mandatory before treatment 1

Side Effects

The most common adverse events with gefitinib are cutaneous toxicity (rash) and gastrointestinal toxicity (diarrhea), which are generally mild but require proactive management to maintain quality of life and prevent treatment discontinuation. 1, 3

Cutaneous Adverse Events:

• Acneiform rash/papulopustular eruption: Occurs in 80.8-89.1% of patients, with grade 3-4 severity in 14.6-16.2% 5
• Dry skin and pruritus: Common manifestations requiring regular emollient use 1
• Paronychia (periungual inflammation): Affects 32.6-56.8% of patients, with grade 3-4 severity in up to 11.4% 5

Gastrointestinal Adverse Events:

• Diarrhea: Occurs in the majority of patients, generally mild 1, 3
• Stomatitis/mucositis: Less common but requires monitoring 1

Serious Adverse Events:

• Tumor hemorrhage: Gefitinib 500 mg/day was associated with more tumor-hemorrhage events compared to methotrexate in head and neck cancer trials 1
• Secondary bacterial infections: Severe skin toxicity disrupts the epidermal barrier, creating portals for bacterial entry and potential cellulitis 5

Management Algorithm:

Grade 1-2 Cutaneous Toxicity:

• Prophylactic intensive moisturization, sun protection, and emollients from treatment initiation 1, 5
• Topical corticosteroids and antibiotics for symptomatic rash 1, 5
• Continue gefitinib without dose modification 1

Grade 3 Cutaneous Toxicity:

• Temporarily discontinue gefitinib 1, 5
• Oral antibiotics and investigation for secondary infection 5
• Resume at reduced dose when toxicity returns to grade 1 or baseline 1

Diarrhea Management:

• Low-fat, low-fiber diet; minimize fruit, red meat, alcohol, spicy food, and caffeine 1
• Loperamide with oral isotonic solution for diarrhea persisting >48 hours 1
• If no improvement, discontinue gefitinib and restart at reduced dose when toxicity returns to grade 1 or baseline bowel habits 1

Critical Clinical Pearls:

• Close follow-up (bi-weekly) during the first 6 weeks of treatment is essential, then monthly thereafter 1
• Dose reductions and treatment interruptions are appropriate strategies to maintain quality of life while preserving clinical benefit 1
• Do not confuse gefitinib-induced papulopustular rash with cellulitis; cellulitis presents with diffuse spreading erythema, indistinct borders, warmth, edema, and systemic symptoms 5
• Gefitinib is generally better tolerated than chemotherapy, with fewer severe adverse events and improved quality of life in mutation-positive patients 1, 6