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M. Nishio



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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-012 - Phase Ia/Ib study of the anti-MET antibody onartuzumab (MetMAb) in patients with solid tumors or MET-positive lung cancer (ID 1164)

      09:30 - 09:30  |  Author(s): M. Nishio

      • Abstract

      Background
      MET, a receptor tyrosine kinase, and its ligand, hepatocyte growth factor (HGF), play a key role in cancer progression and prognosis. Aberrant activation of the HGF/MET pathway can enhance invasion, proliferation, and survival of cancer cells, providing a rationale for developing therapeutics that block MET activation. Onartuzumab was engineered as a unique recombinant humanized one-armed anti-MET monoclonal antibody that inhibits HGF-induced MET signaling without agonistic activity.

      Methods
      This 2-stage study was the first in Japanese patients to evaluate efficacy, safety, and pharmacokinetics (PK) of onartuzumab or onartuzumab in combination with erlotinib. In Stage 1—a 3+3 dose-escalation stage—patients with advanced solid tumors, refractory to the standard of care or for which there is no standard of care, received onartuzumab at doses of 4, 15, or 30 mg/kg IV once every 3 weeks until disease progression. In Stage 2—a combination stage—onartuzumab at a dose of 15 mg/kg IV once every 3 weeks was given in combination with erlotinib 150 mg/day to patients with advanced MET-positive non–small-cell lung cancer who had received at least 1 prior platinum-containing regimen (as regards EGFR-TKI, only 1 regimen was permitted); this regimen was continued until disease progression. Exploratory biomarker analyses were also conducted.

      Results
      In Stage 1, 9 patients (male/female: 6/3) were enrolled. Median age was 68 years. There were no dose-limiting toxicities (DLTs) and the maximum tolerated dose was not reached at 30 mg/kg. Hypoalbuminemia (33.3%) and constipation (33.3%) were the most frequent adverse events (AEs). Hypoalbuminemia was the only AE occurring at grade 3 severity, indicating that onartuzumab was well tolerated up to 30 mg/kg. In Stage 2, 6 patients were enrolled (male/female: 1/5; adeno/squamous: 5/1; EGFR wild type/mutant: 3/3; median age 69 years). There were no DLTs. The most frequent AE was diarrhea (83.3%). Grade 1/2 AEs occurred in all patients. There was one grade 3 case of each of deep vein thrombosis, pulmonary embolism, rash, hypoxia, dermatitis acneform, diarrhea, and neutropenia. No grade 4/5 AE was observed. PK analysis from patients in Stages 1 and 2 indicated dose proportionality of C~max~ and AUC. No drug–drug interaction between onartuzumab and erlotinib was observed. In Stage 2, progression-free survival was beyond 6 months in 2 patients (7.2 and 12.2 months); 1 patient achieved a partial response. Median circulating HGF concentration after onartuzumab was elevated to approximately three times the baseline level.

      Conclusion
      Onartuzumab alone or with erlotinib was well tolerated in Japanese patients. The PK profile of onartuzumab was not affected by co-administration with erlotinib.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-010 - Patterns of relapse and prognosis after crizotinib therapy failure in ALK+ Non-small cell lung cancer (ID 983)

      09:30 - 09:30  |  Author(s): M. Nishio

      • Abstract

      Background
      Although crizotinib which is a first-in-class oral ALK inhibitor shows dramatic response and prolonged PFS in patients with ALK(+) NSCLC, most of the patients relapsed within one year. However, patterns of relapse, prognosis, and outcome of further therapy after crizotinib failure have not been well examined.

      Methods
      We identified patients at our hospital with ALK(+) NSCLC who received and failed in crizotinib therapy.

      Results
      There were 20 patients (11 females and 9 males, with a median age 48 years). ALK fusion gene was confirmed by IHC and/or FISH (17 patients IHC+/FISH+, 3 patients FISH+). The median treatment duration of crizotonib was 4.5 months (range, 1.1-18.6 months) and the median overall survival (OS) after discontinued on crizotinib was 4.8 months; 13 patients died. At the time when crizotinib was discontinued, 2 patients (10%) had progressive disease (PD) at the primary site of disease (local recurrence), 18 patients (90%) had PD of distant metastasis and one patient had PD at both the primary site and distant metastasis. PD in CNS was observed in 9 patients. Re-biopsies after failure of criztotinib were performed in 3 patients. Two secondary mutation were identified in 2 of 3 pts (L1196M (n = 1) and G1269A (n = 1). Eleven of 20 patients received additional chemotherapy (7 cytotoxic chemotherapies and 4 ALK-inhibitor). Two of 7 patients who received cytotoxic chemotherapy (included docetaxel, S-1, cisplatin+pemetrexed+bevacizumab and carboplatin+pemetrexed) after crizotinib had PR (28.5%).

      Conclusion
      After crizotinib therapy failure, PD most commonly occurred at distant metastasis especially CNS in ALK+ NSCLC patients. Cytotoxic chemotherapy after crizotinib failure provide only minimum responses. A New effective therapeutic strategy after failure of crizotinib is necessary in ALK+ NSCLC patients.