Table 2 Predictive biomarkers in the major clinical trials

TKI

INTEREST [35]

Gefitinib vs. Docetaxel in previous treated patients

EGFR mutation predicted for longer PFS and higher ORR (p <0.05) and high EGFR copy number predicted for higher ORR (p <0.05) with Gefinitib vs. Docetaxel. KRAS mutation was not predictive for response or survival.

SATURN [36]

Maintenance Erlotinib vs. observation after 1^st line chemotherapy

EGFR IHC, EGFR FISH, KRAS mutation and EGFR CA-SSR1 repeat length status did not predict for drug response. EGFR mutation predicted for PFS, and OS benefit after Erlotinib treatment KRAS mutation predicted for poor PFS.

Italian Phase II study [37]

EGFR-TKI as 2^nd line treatment

pAKT and HER-2 expression are the only independent predictors of PFS and OS

ERMETIC [38]

EGFR TKI as 1^st, 2^nd, or 3^rd line treatment

Median PFS: EGFR mutant 8.4 mo, EGFR wild type 2.3 mo, KRAS mutant 1.9 mo, p = 0.001. Median OS: EGFR mutant 14.4 mo, EGFR wild type 5.3 mo, KRAS mutant 4.1 mo, p = 0.004.

PUMC prospective study [39]

Gefitinib after failing 1^st line chemotherapy

EGFR mutation is the only independent predictor of tumor response.

IDEAL & INTACT trials [40]

IDEAL trials: phase II studies on Gefitinib as 2^nd line treatment; INTACT trials: phase III studies investigating the benefit of adding Gefitinib to chemotherapy as 1^st line treatment

EGFR mutation predicted for increased response to Gefitinib in IDEAL trials, but not in the INTACT trials. KRAS mutation, PTEN mutation or expression and p53 expression not associated with clinical response to Gefitinib in the IDEAL trials.

TRIBUTE [41]

Carboplatin + Taxol (CT) vs. CT + Erlotinib; followed by Erlotinib maintenance

EGFR mutations (13%) in EGFR exons 18 through 21 were predictive of OS overall; and superior response to CT + Erlotinib (p <0.01). KRAS mutations (21%) at KRAS exon 2 was associated with decreased TTP and OS in the CT + Erlotinib arm.

IPASS (Fukuoka JCO 11) [42] Non smokers or former light smokers with adenocarcinoma

Carboplatin + Taxol vs. Gefitinib

High EGFR gene copy number was associated with increased PFS and ORR after Gefitinib vs. Carbo/Taxol. However, it predicted for poorer PFS in the absence of EGFR mutation. EGFR mutation at Exon 19 and 21 predicted for superior PFS and ORR after Gefitinib.

Cetuximab

SWOG 0342 [43]

Carbo/Taxol + Cetuximab vs. Carbo/Taxol; Both followed by Cetuximab for 1 year

Increased EGFR gene copy numbers is associated with superior PFS and OS (p <0.05)

BMS099 [44]

Carboplatin + Taxane (CT) vs. CT + Cetuximab

EGFR FISH, EGFR IHC, KRAS mutations and EGFR mutations did not predict for ORR, PFS, or OS benefit with the addition of Cetuximab

FLEX [45]

Cisplatin + Vinorelbine (CV) vs. CV + Cetuximab

KRAS (19%), EGFR FISH + (37%), PTEN negativity (35%) were of no predictive value. EGFR mutation (15%) predicted for improved OS in both arms (p <0.05).