AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).

Human NSCLCs with activating mutations in EGFR frequently respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib but responses are not durable as tumors acquire resistance. Secondary mutations in EGFR (T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence of epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with erlotinib acquired resistance in the absence of EGFR T790M or MET activation. Genetic or pharmacologic inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL, and in some cases its ligand GAS6, was found in EGFR-mutant lung cancers obtained from patients with EGFR TKI acquired resistance. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome EGFR TKI acquired resistance in EGFR-mutant lung cancer patients.

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Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

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Implications of all the available evidence Entrectinib is an important therapeutic option for patients with ROS1 TKI-naïve ROS1 fusion-positive NSCLC. The intracranial activity of entrectinib is of particular importance, given the frequency of CNS involvement in ROS1 fusion-positive NSCLC and the limited ability of crizotinib to penetrate the CNS.