boring the L858R/T790M double mutant, and in models dependent on HER2 overexpression.47 Afatinib 40–50 mg/day was evaluated in a single-arm phase II trial (LUX-Lung 2) in patients with advanced lung adenocarcinomas harboring activating EGFR mutations.49 Target accrual was 120 patients, with a total of 129 patients treated with afatinib— 68 in the second-line and 61 in the first-line setting; most patients were Asian (n = 112) and never smokers (n = 82).49 In the overall population, DCR was 86%, confirmed objective RR was 60%, median PFS was 14 months, and median ABT-263 OS was 24 months.50 DCR, confirmed objective RR, and PFS were 83%, 59%, and 16.1 months, respectively, in patients with L858R EGFR mutations (n = 54) and were 93%, 69%, and 13.7 months, respectively, in patients with a deletion in exon 19 of EGFR (n = 52).

Diarrhea and rash/acne were the most common drug-related adverse events (AEs), occurring in 95% (19% at grade 3) and 91% (21% at grade 3) of patients, respectively.50 Afatinib was evaluated in a phase IIb/III trial (LUX-Lung 1) in patients with advanced lung adenocarcinoma who had failed 1 or 2 lines of chemotherapy and progressed after P12 weeks of therapy with erlotinib or gefitinib.51 Between May 2008 and September 2009, 585 patients were randomized and received best supportive care plus either afatinib or placebo. Median OS (the primary endpoint) was 10.78 months with afatinib vs 11.96 months with placebo (HR, 1.08; 95% CI, 0.86–1.35). However, afatinib significantly prolonged PFS (a secondary endpoint) to 3.3 months (vs 1.1 with placebo; HR, 0.38, P < 0.0001) in this population that was clinically enriched for the presence of ABT-263 Bcl-2 inhibitor EGFR-activating mutations. Afatinib was also associated with significant improvements in the secondary endpoints of confirmed DCR of at least 8 weeks (58% vs 19%; P < 0.0001) and confirmed objective RR (11% vs 0.5% by investigator analysis and 7.4% vs 0.5% by independent analysis; P < 0.01). The 2 most common AEs observed with afatinib were diarrhea (87%; 17% at grade 3) and rash/acne (78%; 14% at grade 3). Afatinib is being evaluated in an exploratory phase II study in patients with advanced NSCLC who were never smokers or light ex-smokers and who fall into 1 of 3 categories: (1) tumor harboring EGFR/HER1 mutation and prior erlotinib or gefitinib failure, (2) tumor with EGFR/HER1 FISH positivity and prior erlotinib or gefitinib failure, or (3) tumor harboring HER2 mutation.52

In a preliminary report of this study, all 3 evaluable patients were female, nonsmokers, had failed prior chemotherapy, and had tumors harboring mutations in the kinase domain of HER2. All 3 patients achieved PRs with afatinib 50 mg/day with ABT-263 923564-51-6 concomitant improvements in symptoms and performance status.52 A randomized, open-label, phase III study (LUX-Lung 3) is also evaluating afatinib vs pemetrexed/ cisplatin as first-line therapy in patients with NSCLC tumors harboring EGFR-activating mutations (NCT00949650). Another randomized, open-label, phase III study (LUX-Lung 6) is evaluating afatinib vs cisplatin/gemcitabine chemotherapy as first-line therapy in patients with EGFR mutations in China, Korea, and India (NCT01121393). Afatinib is also being explored in combination with cetuximab for NSCLC. Preclinical analyses showed the combination was associated with CRs in mice with tumors harboring the T790M mutation or the L858R mutation.53 A phase I trial to evaluate the combination of afatinib with cetuximab is currently recruiting NSCLC patients with progressive disease following treatment with erlotinib or gefitinib (NCT01090011).

PF-00299804 PF-00299804 is an irreversible pan-HER TKI that inhibits the kinase activity of wild-type EGFR (IC50, 6 nM), HER2 (IC50, 45.7 nM), and HER4 (IC50, 73.7 nM).48 It is effective against NSCLC cell lines with the following double mutations: EGFR exon 19 deletion and L858R mutation and L858R/T790M mutations.48 PF-00299804 has shown activity in NSCLC cell lines with HER2 amplification an