Navitoclax  those carrying the HER2 Ins774YVMA insertion mutation, but not in those with KRAS mutations.48 In an NSCLC cell line harboring the EGFR T790M mutation that maintained HER3/PI3K/Akt phosphorylation, PF-00299804, but not gefitinib, completely inhibited the HER3 signaling pathway and caused substantial apoptosis. 48 Similarly, in tumor xenograft models harboring the EGFR T790M mutation, PF-00299804, but not gefitinib, was effective in inhibiting tumor growth.48 PF-00299804 was also evaluated in A431 human squamous cell carcinoma and H125 human NSCLC xenograft models.54 In the A431 xenografts, PF-00299804 was administered once daily for 14 days, producing an average tumor growth delay of 45 days at a dose of 11 mg/kg. Several animals had a PR or a CR, defined as reductions in tumor mass of P50% and P75% from baseline, respectively, at doses of 11–100 mg/kg. In H125 xenografts, PF- 00299804 at doses of 30 or 65 mg/kg once daily for 14 days produced tumor growth delays of 9.1 and 10.2 days, respectively, although none of the animals had a PR or a CR. In these models, mean body weight declined by approximately 20% in animals treated with PF-00299804 at doses of 30 mg/kg or more.54 In a 2-arm, phase

II trial evaluating PF-00299804 in patients with advanced NSCLC who had failed 1 or 2 prior chemotherapy regimens as well as prior treatment with erlotinib, patients with adenocarcinomas were enrolled in 1 arm of the study and patients with other NSCLC histologies were enrolled in the other arm.55 Preliminary results have been reported for the first 66 patients: 44 patients with adenocarcinomas and 22 patients with nonadenocarcinomas. 55 As of August 2009, of 36 evaluable patients with adenocarcinoma and 5 patients with non-adenocarcinoma, the DCR was 67% and 40%, respectively; SD >6 months occurred in 2 patients with adenocarcinoma and 1 patient with non-adenocarcinoma. 55 The most common Navitoclax 923564-51-6

AEs of any grade were diarrhea (82%), skin toxicity (77%), fatigue (59%), stomatitis (28%), and vomiting (23%).55 This study suggests that PF-00299804 may have clinical activity in patients with advanced NSCLC after the failure of prior chemotherapy and erlotinib. In the first-line setting, PF-00299804 is being tested in a phase II, open-label trial in patients with advanced lung carcinoma who were never smokers or former light smokers.56 Among the first 29 evaluable patients, there was 1 CR, 6 PRs, and 16 patients with SD for P16 weeks. In a subanalysis of 14 evaluable patients with EGFR mutation-positive disease, tumor shrinkage was observed in all cases. The most common treatment-related AEs were diarrhea and dermatitis acneiform for all grade events (79% and 49%, respectively) and grade 3 events (9% for both). Another phase II trial evaluated PF-00299804 vs erlotinib as second-line or third-line therapy in 188 patients with advanced NSCLC. PF-00299804 was associated with improvements in median PFS (HR, 0.681; 95% CI, 0.490–0.945; P = 0.019) and objective buy Navitoclax

RR (17.0% vs 4.3%; P = 0.009) and clinical benefit rate (response or SDP24 weeks; 27.7% vs 13.8%; P = 0.03).57 However, there were imbalances between treatment arms of this study in the percentage of patients with performance status of 2 (PF-00299804, 19.1% vs erlotinib, 3.2%) and with tumors harboring EGFR mutations (PF-00299804, 20.2% vs erlotinib, 11.7%).57 PF-00299804 is being evaluated in patients with KRAS wild-type NSCLC refractory to at least 1 chemotherapy regimen and erlotinib in another phase II study.58 Among 62 evaluable patients, 3 achieved a PR and 35 had SD. AEs included diarrhea (86%), fatigue (40%), rash (45%), and stomatitis/mucosal inflammation (23%). In Korea, an open-label, single-arm, phase I/II trial is evaluating PF- 00299804 in patients with advanced NSCLC and wild-type KRAS who have failed treatment with chemotherapy and an EGFR TKI.59 For 42 patients in the phase II portion, preliminary results demonstrated an objective RR of 15%, clinical benefit rate (PR or SD (P24