acokinetics of erlotinib alone or combined with PF-02341066 in patients with advanced NSCLC of adenocarcinoma histology (NCT00965731). As ALK alterations are reciprocally exclusive of EGFR mutations,88 these agents may be useful in patients with EGFR wild-type tumors that are less sensitive to first-generation EGFR TKIs. A number of monoclonal antibodies and TKIs have been developed that target the IGF-1R.89 Of these, the most advanced in clinical development for NSCLC is the anti-IGF-1R monoclonal AZD6244 antibody figitumumab (CP-751,871 [Pfizer; New London, CT, US]).90,91 In a phase II trial, patients (N = 156) with previously untreated advanced NSCLC were randomly allocated in a 2:1 ratio to receive paclitaxel/carboplatin with or without figitumumab (10– 20 mg/kg) every 3 weeks for up to 6 cycles.90 Overall RR was 54% in the paclitaxel/carboplatin plus figitumumab arm compared with 42% in the chemotherapy alone arm (P < 0.0001). Exploratory analyses by dose and histology revealed that among

patients with squamous cell carcinomas and adenocarcinomas, overall RR was 62% in patients who received paclitaxel/carboplatin plus figitumumab 20 mg/kg vs 33% in patients who received chemotherapy alone (P = 0.0478).90 The addition of figitumumab 20 mg/kg to chemotherapy also provided improved PFS compared with chemotherapy alone (HR, 0.46; 95% CI, 0.18–0.75; P = 0.0058). RRs and PFS did not differ for patients with unspecified histologies. Grade 3/4 hyperglycemia was noted in 15% and 8% of AZD6244 ARRY-142886 patients in the combination and chemotherapy alone arms, respectively.90 Patient enrollment in a phase III clinical trial testing figitumumab in combination with paclitaxel/carboplatin was halted for futility.92 Serious AEs in the combination arm included dehydration, hyperglycemia, and hemoptysis. The heat shock protein (HSP) 90 chaperone mediates conformational changes for the EGFR family, MET, and various downstream kinases, including Akt.93 HSP90 inhibitors may be a viable strategy for the treatment of NSCLC because EGFR mutations associated with resistance to first-generation EGFR TKIs do not compromise the ability of HSP90 to regulate

EGFR family members.93 HSP90 inhibitors have been shown to suppress EGFR-mediated signaling in erlotinib-sensitive and erlotinib-resistant cell lines, including those with L858R/T790M double mutation.93 Moreover, in these resistant cells, HSP90 inhibitors prevented signaling by MET- and IGF-1R–dependent mechanisms. IPI-504 (Infinity Pharmaceuticals; Cambridge, MA, US), an HSP90 inhibitor, is being evaluated in a phase I/II trial (NCT00431015) in patients with relapsed or refractory NSCLC. The mammalian target of rapamycin (mTOR) inhibitor everolimus (Novartis; Cambridge, MA, US) was evaluated in a phase II trial of patients with advanced NSCLC who progressed after 62 prior chemotherapy regimens or chemotherapy plus a first-generation EGFR AZD6244 MEK inhibitor TKI.94 Patients received everolimus 10 mg/day until PD or unacceptable toxicity. Everolimus produced objective responses in 7.1% of patients who had previously failed chemotherapy and in 2.3% of patients who had failed chemotherapy and an EGFR TKI. Overall, everolimus provided disease control in 47% of patients; median PFS was 2.7 and 2.6 months in the subgroups who had and had not received prior

EGFR TKI therapy, respectively. Fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia were the most frequently reported gradeP3 AEs that were associated with everolimus.94 A phase I trial is being conducted to explore the feasibility of adding everolimus to carboplatin/paclitaxel as first-line therapy in patients with NSCLC.95 In a phase I/II trial evaluating everolimus plus erlotinib vs erlotinib alone in 133 patients with advanced NSCLC who progressed after P2 prior lines of chemotherapy, preliminary results demonstrate a 3-month DCR of 39.4% vs 28.4% and a median PFS of 2.9 months vs 2.0 months, respectively. In the combination group, the most common grade 3/4 AEs reported in P4 patients