able patients, 10 (28%) achieved a PR; of those, 7 had EGFR-activating mutations detected in their tumor tissue. Common AEs included grade 1 or 2 diarrhea, rash, fatigue, nausea, and clinically asymptomatic QTc prolongation.76 No new trials evaluating XL647 in NSCLC patients are planned. Several inhibitors of signaling pathways that complement the EGFR pathway are also being evaluated in clinical trials in patients with advanced Veliparib NSCLC. In vitro analyses conducted by Zucali and colleagues showed that DN-30, an anti-cMET monoclonal antibody, acted synergistically with hepatocyte growth factor to enhance the inhibition of growth by gefitinib in activated cMET [pY1003]- expressing cell lines.35 In addition, blockade of cMET with a cMET TKI (PHA-665752) restored the sensitivity of NSCLC cells to gefitinib.32 Several MET inhibitors (ARQ 197 [ArQule, Inc.; Woburn, MA, US], XL184 [Exelixis; South San Francisco, CA, US], and MetMAb [Genentech; South San Francisco, CA, US]) are Veliparib 912444-00-9

being tested in phase II trials in combination with erlotinib in patients with NSCLC (NCT00777309, NCT00596648, and NCT00854308, respectively). ARQ 197 is a non-ATP competitor of the MET protein, and has shown preliminary clinical activity as monotherapy77,78 and in combination with erlotinib79 in phase I clinical trials. In 1 trial, ARQ 197 was administered in 21-day cycles at escalating doses of 120 mg, 240 mg, and 360 mg twice daily in combination with erlotinib 150 mg/day.79 Although no objective responses were observed in 25 treated patients with solid tumors, 3 of 3 evaluable patients with NSCLC achieved SD for durations of 14–32 weeks. Two patients experienced treatment-related serious AEs: neutropenia with the 360-mg dose and sinus bradycardia with the 240- mg dose.79 Data from a global randomized phase II trial of erlotinib plus ARQ 197 or placebo (N = 167) indicated a non-significant improvement PFS in the ARQ 197 arm (16.1 vs 9.7 weeks in the placebo arm;

HR, 0.81; 95% CI, 0.57–1.15; P = 0.23).80 However, a significant PFS benefit was demonstrated in a planned multivariable Cox regression model that adjusted for histology and genotype (for which imbalances were observed at baseline) and other prognostic buy Veliparib factors (HR, 0.68; 95% CI, 0.47–0.98; P < 0.05); improvements in PFS were observed among patients with non-squamous histology and with tumors harboring wild-type EGFR or KRAS mutations. In both arms, rash and diarrhea were the most common all-grade AEs, with similar incidences between the arms (64% and 52% for rash; 48% and 53% for diarrhea). XL184, a small molecule MET TKI, has shown preclinical activity as monotherapy in EGFR TKI-resistant cell lines and in HCC827GR6 xenograft tumors when administered in combination with erlotinib. 81 Finally, MetMAb is a monovalent antagonist antibody to the MET receptor that has demonstrated preclinical activity in pancreatic82 and glioblastoma models.83–85 Data demonstrating the effects of XL184 or MetMAb in patients with NSCLC have not yet been presented. PF-02341066 (Pfizer; New London, CT, US) is an inhibitor of the MET and anaplastic lymphoma kinase (ALK) TKs;

it has been estimated that 1–6% of unselected patients with NSCLC have tumors with an echinoderm microtubule-associated protein like-4 (EML4)-ALK translocation.86 Results were recently presented for a 2-part phase I trial of PF-02341066 in patients with ALK fusionpositive advanced NSCLC with varying extent of pretreatment (median of 3 prior regimens), for which the RR was 64% and DCR was 90% among the first 50 evaluable patients.87 Monotherapy with PF-02341066 vs docetaxel or pemetrexed (investigator choice) is being evaluated in an ongoing phase III study in patients with NSCLC harboring an ALK aberration (NCT00932893). Patients progressing on chemotherapy in this phase III trial may be considered for inclusion in a single-arm phase II trial of PF-02341066 as monotherapy (NCT00932451). Also ongoing is a phase I/II trial of the safety, efficacy, and pharm