Author of

• 11745

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

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 2
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11757

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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): Y. Kawano
    • 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.

  • 11765

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    P2.11-020 - Sorafenib in patients with RET fusion-positive non-small cell lung cancer (ID 1717)

    09:30 - 09:30  |  Author(s): Y. Kawano
    • Abstract

    Background
    RET fusions were recently identified in non-small cell lung cancer (NSCLC) and considered to be a druggable target of NSCLC. There are several small molecules which can potentially inhibit RET kinase activity. Among them, sorafenib, sunitinib and vandetanib are clinically available, and sorafenib is the most promising agent which showed potent anti-RET activity (the IC50 against RET is 0.0059-0.047 μM) in preclinical studies. However, it is difficult to evaluate the efficacy of this agent in RET-positive NSCLC in large clinical trials, because RET-positive NSCLC makes up only 1% to 2% of NSCLC cases. Therefore, we conducted a pilot study to evaluate the efficacy and feasibility of sorafenib treatment in a small number of patients with RET fusion-positive NSCLC.

    Methods
    Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an ECOG performance status (PS) 0–2, adequate organ function and provided informed consent. The RET fusion gene was confirmed by a split FISH assay. Patients received 400 mg of sorafenib orally twice daily. The treatment was continued until disease progression or unacceptable toxicity.

    Results
    From March 2012 to April 2013, three patients were enrolled. The first patient was a 62-year-old female who had stage IV NSCLC and had received three prior chemotherapy regimens (pemetrexed with cisplatin, docetaxel and erlotinib) and two courses of palliative radiation (thorax and whole brain) before being enrolled this study. The second patient was a 38-year-old male who had recurrence after thoracic surgery and had received two prior chemotherapy regimens (pemetrexed with cisplatin and docetaxel) and whole brain radiation before enrolling this study. The third patient was a 75-year-old female who had recurrence after thoracic surgery and had received one prior chemotherapy regimen (Docetaxel). The pathological diagnoses were adenocarcinoma in two patients and NSCLC not otherwise specified in one patient. Their tumors did not demonstrate any EGFR mutations or ALK fusion. The RET partner genes were KIF5B in two patients and unknown in one patient. All three patients were treated with sorafenib at 400 mg orally twice daily. Unfortunately, there was no response. The best responses to sorafenib in the patients were PD, SD and SD. In the third patient, sorafenib treatment was continued for over seven weeks. The most common toxicities were hand-foot syndrome, hypertension and diarrhea. The third patient needed a dose reduction to 400 mg once daily due to grade 3 hand-foot syndrome.

    Conclusion
    Sorafenib seems to have some efficacy for the RET fusion-positive NSCLC, but no dramatic response was observed.