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L.P. James

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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.07 - Combined pan-ERBB and ALK/ROS1/MET inhibition with dacomitinib and crizotinib in advanced non-small cell lung cancer (NSCLC): update of a phase I trial (ID 2740)

      16:15 - 17:45  |  Author(s): L.P. James

      • Abstract
      • Presentation
      • Slides

      EGFR T790M mutation and MET amplification have been implicated as mechanisms of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in advanced NSCLC. We evaluated the feasibility of combining dacomitinib and crizotinib to overcome acquired resistance in patients with NSCLC whose last prior treatment was either single-agent erlotinib or gefitinib. Dacomitinib is an orally bioavailable, irreversible, small-molecule inhibitor of all kinase-active HER-family tyrosine kinases (EGFR/HER1, HER2, and HER4) with in vitro activity against T790M-mutated EGFR. Crizotinib is an ALK, ROS1, and MET TKI with demonstrated efficacy in the treatment of advanced ALK-positive and ROS1-positive NSCLC and several MET-amplified tumor types. Here we update previous data reported for PROFILE 1006 (Jänne et al, ESMO 2012; Pfizer, NCT01121575).

      The study comprised a 3+3 design dose-escalation phase followed by an expansion phase of two concurrent cohorts: A) combined dacomitinib plus crizotinib and B) single-agent dacomitinib until progression, followed by combined dacomitinib plus crizotinib. The study enrolled patients with advanced NSCLC who had progressed after ≥1 line of chemotherapy/targeted therapy. The expansion phase was restricted to patients with acquired resistance to single-agent erlotinib or gefitinib, which was defined as PD following either a response or SD for 6 months. Patients in the expansion phase had a mandatory tumor biopsy for biomarker analysis at study entry. Endpoints included safety, best overall objective response rate (ORR), progression-free survival, and biomarkers in tumor and blood that are potentially predictive of antitumor activity.

      33 patients were enrolled in the dose-escalation phase of the study. Dose-limiting toxicities (DLTs) were the following grade 3 events: diarrhea (n=1), elevated ALT (n=1), and mucositis (n=1). The dacomitinib 30 mg qd plus crizotinib 200 mg bid combination showed no DLTs in 10 evaluable patients and was taken forward into the expansion phase. At the time of data cut-off on 31 December 2012, 27 patients had enrolled in the expansion phase (23 in cohort A and 4 in cohort B). Patient characteristics were as follows: M/F, 11/16; median age, 60 years (range 42–82); ECOG PS 0/1/2, 4/19/4; Caucasian/Asian, 22/5; never-smokers/ex-smokers/smokers, 18/7/2; number of prior systemic therapies 1/2/3/>3, 9/8/3/6. Nine patients (33%) in the expansion phase had started ≥4 cycles (approximately 12 weeks) of the combination. There were 20 evaluable patients in expansion cohort A, with an ORR of 5%. A further 8 patients (40%) experienced SD, and 1 of these patients had an unconfirmed PR. Tumor samples were available for biomarker analyses from 18 patients in expansion cohort A. Analyses to date revealed 1/17 patient samples had MET amplification (MET:CEP7 ratio >2); 1/5 had EGFR amplification; 7/12 harbored the EGFR T790M mutation; 1/11 displayed a KRAS mutation; 18/18 were negative for ALK rearrangement by FISH.

      The dacomitinib 30 mg qd plus crizotinib 200 mg bid combination was administered with a manageable tolerability profile and was associated with clinical activity in patients with EGFR TKI-resistant advanced NSCLC. Analysis of predictive tumor biomarkers is underway in all patients in the expansion phase.

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