TKI

Generation (Gen)

Study

Finding

S/E

Erlotinib

1st gen

OPTIMAL trial: Erlotinib versus gemcitabine + carboplatin [42]

EURTAC trial: Erlotinib vs platinum-based chemotherapy doublet [43]

ENSURE trial: Erlotinib or gemcitabine and cisplatin [44]

PFS 13.1 versus 4.6 months (HR 0.46, 95% CI 0.37-0.57)

Response Rate 83 vs 36%

PFS 9.7 versus 5.2 months (HR 0.16, 95% CI 0.10-0.26)

PFS 11.0 versus 5.5 months (HR 0.34, 95% CI 0.22-0.51)

Rash, Diarrhea,

LFT elevation, Nausea and vomiting

Gefitinib

1st gen

IPASS trial: gefitinib or carboplatin plus paclitaxel [45]

12-month progression-free rate 25 versus 7 percent, HR for progression 0.74

Patients with EGFR mutation had better PFS with gefitinib however those without EGFR mutation, PFS was shorter with gefitinib

Acne-like rash, diarrhea, stomatitis, elevation of liver enzymes, interstitial lung disease

Afatinib (Irreversible)

2nd gen

Phase III Lux-Lung 3 trial: Afatinib or cisplatin plus pemetrexed [46]

Phase III trial Lux-Lung 6: afatinib or gemcitabine plus cisplatin [47]

12 month progression-free rate 51 versus 21 percent, HR for progression 0.58, 95% CI 0.43-0.78

PFS 11.0 versus 5.6 months

Diarrhea, rash, stomatitis, paronychia, and dry skin

Dacomitinib

2nd gen

Phase III trial ARCHER 1050: Dacomitinib versus gefitinib [48]

Mok et al. [49]

At 22 months PFS was 14.7 versus 9.2 months; HR 0.59, 95% CI 0.47-0.74

At 31 months OS was 34 versus 27 months; HR 0.76, 95% CI 0.58-0.99

Grade 3-4 dermatitis, grade 3-4 diarrhea

Osimertinib

3rd gen

Phase III FLAURA trial: Osimertinib versus standard of care [50]

PFS 18.9 versus 10.2 months

Response Rate 80 versus 76%

QT prolongation, reduction in EF