Table 2. Different tyrosine kinase inhibitors and monoclonal antibodies that are approved or in clinical trial/discontinued for non-small-cell lung cancer therapy.

Therapy	Mechanism of action	Stage of development	Adverse effects†
First-generation TKIs
Gefitinib [53]	Reversible EGFR TKI	US FDA approved in 2003; withdrawal of approval in 2005 due to lack of survival benefit	Rash, vomiting, stomatitis, dehydration
Erlotinib [54]	Reversible EGFR TKI	FDA approved for metastatic NSCLC in 2014	Rash, diarrhea, loss of appetite, rarely interstitial pneumonitis
Second-generation TKIs
Afatinib [21]	Irreversible EGFR (including T790M mutant EGFR), HER2 and HER4 TKI	FDA approved	Diarrhea, stomatitis, dermatitis acne form, decreased appetite, dry skin, nose bleed
Dacomitinib [55]	Irreversible TKI targeting EGFR, HER2, HER4	Phase III, disappointing results in terms of superiority	Diarrhea, acne form dermatitis, fatigue, stomatitis, rash, dry skin
Neratinib [56,57]	Irreversible EGFR and HER2 TKI	Phase II, poor bioavailability, diarrhea related dose limitation	Severe diarrhea toxicity
Third-generation TKIs
Poziotinib [58]	Irreversible mutant EGFR TKI	Phase II	Diarrhea, stomatitis, rash, dermatitis acneiform, anorexia, dry skin
AZD9291 [59]	Irreversible mutant EGFR TKI	Phase I	Diarrhea, rash, nausea
CO-1686 [60]	Irreversible mutant EGFR TKI	Phase II	Hyperglycemia, nausea, diarrhea, decreased appetite, vomiting, fatigue, myalgia
Monoclonal antibodies
Cetuximab [61]	Monoclonal antibody against EGFR	Phase III	Breathing difficulty, low blood pressure, acne-like rash
Necitumumab [62]	Monoclonal antibody against EGFR	Phase III in combination with gemcitabine-cisplatin chemotherapy
Panitumumab [63]	Human monoclonal antibody against EGFR	Phase II in combination with carboplatin and pemetrexed	Nausea, fatigue, rash, thrombocytopenia, neutropenia, dehydration
Nimotuzumab [64]	Humanized monoclonal antibody to EGFR	Phase II along with radiation ordocetaxel and cisplatin	Fatigue, anorexia, chills, pain, hypophosphatemia
Matuzumab [65]	Humanized monoclonal antibody to EGFR	Phase II in combination with paclitaxel, development discontinued
Zalutumumab [66]	Human monoclonal antibody against domain III of EGFR	Phase II discontinued
Combination therapies
Pertuzumab + erlotinib [67,68]	Pertuzumab–HER2 dimerization inhibitor Erlotinib–EGFR TKI	Phase II	Pneumatosis intestinalis
Cetuximab + erlotinib [69]	Cetuximab–anti-EGFR antibody that prevents EGFR activation Erlotinib–EGFR TKI	Phase II	Rash, fatigue, hypomagnesemia
Trastuzumab + pertuzumab [70]	Trastuzumab–antibody-dependent cellular cytotoxicity, blockade of HER2 signals Pertuzumab–HER2 dimerization inhibitor	Preclinical

^†Adverse effects were cited from clinicaltrials.gov.

EGFR: EGF receptor; NSCLC: Non-small-cell lung cancer; TKI: Tyrosine kinase inhibitor.