weeks  of 25%, and a 4-month and 6-month PFS rate of 48% and 32%, respectively. Treatment-related diarrhea (grade 3, 14.3%), paronychia (grade 3, 7.1%), and rash, stomatitis, pruritus and dermatitis acneiform (grade 3; all 2.4%) were the most common AEs observed.Lapatinib is a reversible dual EGFR/HER2 TKI that has been evaluated for the treatment of NSCLC. Two schedules of lapatinib (1500 mg once daily and 500 mg twice daily) were evaluated as first-line or second-line treatment in a phase II multicenter trial in patients with advanced NSCLC.60 Among 56 patients with bronchioloalveolar carcinoma histology or no smoking history, ABT-869  there were no objective responses and 14 patients (25%) had SD for P24 weeks. Of the remaining 75 patients, which included patients with other histologies or a smoking history, 1 (1.3%) had a PR and 16 (21%) had SD. Three patients with EGFR mutations failed to respond to lapatinib, although 1 of 2 patients with HER2 amplification did achieve a 51% decrease in tumor size

(albeit unconfirmed). There were no notable differences in the most common treatment-related AEs between the 2 dose schedules (1500 mg vs 500 mg), which included diarrhea (60% vs 50%), rash (48% vs 41%), fatigue (37% vs 30%), nausea (38% vs 24%), and anorexia (26% vs 23%).60 However, the trial was stopped due to lack of efficacy after 131 patients had been randomized to 1 of the 2 lapatinib schedules.61 Results from this study suggest that lapatinib has limited single-agent activity in patients with advanced NSCLC. Neratinib (HKI-272) is an irreversible EGFR/HER2 TKI.62 In a 3- arm phase II trial, patients with advanced NSCLC were assigned to receive neratinib if they progressed afterP12 weeks of erlotinib or gefitinib therapy and had tumors with an EGFR mutation (arm A) or wild-type EGFR (arm B), or if they had never received an EGFR TKI but had adenocarcinoma and a light (620 pack-year) smoking history (arm C).

62 Patients initially received neratinib 320 mg/day, but the dose was decreased to 240 mg/day because of dose delays and reductions associated with diarrhea. Overall, 3 (1.9%) of 158 patients had objective responses and 14 (9%) of 158 patients had SD for P6 cycles (24 ± 2 weeks), with an objective RR of 3.4% for arm A and 0% for arms B and C. Overall median PFS was 15.3 weeks (90% CI, 14.7–15.9) and was 15.3 (90% CI, 11.9–15.7), 16.1 (90% CI, 15.0–23.9), and 9.3 (90% CI, 6.4–18.9) weeks in arms A, B, and C, respectively. The most common neratinib-related AEs, regardless of grade, were diarrhea (91%), nausea (55%), fatigue (37%), vomiting (35%), anorexia (32%), and abdominal pain (32%); grade 3/4 AEs with an incidence P5% were limited to diarrhea (28%) and dyspnea (11%).62 Thus, neratinib demonstrated limited efficacy in patients who were previously treated with first-generation EGFR TKIs and is no longer in development for the treatment of NSCLC. Reasons underlying the modest clinical activity of lapatinib and neratinib in NSCLC are unknown, especially in light of robust responses observed in other cancers (e.g., breast cancer).63–66 One explanation may be that breast cancer is a largely HER2-driven disease, and buy ABT-869

HER2-resistance mutations have not yet been identified. In addition, the role of EGFR in breast cancer has not been fully established. Similarly, EGFR-activating mutations akin to those scribed in NSCLC have not yet been identified in breast cancer. The strong EGFR-driven component of NSCLC combined with the development of resistance likely precludes the prolonged use of reversible or weak irreversible inhibitors in NSCLC. For example, Godin- Heymann and colleagues showed that cells harboring an EGFR T790M mutation were resistant to neratinib and that this resistance could only be overcome with suprapharmacologic concentrations of neratinib (P1 lM).67 In the phase II trial by Besse and colleagues, 12 patients (7%) had T790M mutations, and none responded to neratinib.62 These findings suggest that the treatment of advanc purchase ABT-869