1708PD - Molecular profile and anti-tumor activity in non-small cell lung cancer (NSCLC) patients (pts) in a phase 1 study of cabozantinib (XL184) in Japan

Date 30 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Clinical research
Pathology/Molecular Biology
Non-small-cell lung cancer
Basic Scientific Principles
Presenter Hiroshi Nokihara
Authors H. Nokihara1, N. Yamamoto2, S. Nakamichi2, H. Wakui2, Y. Yamada3, J. Frye4, A. DeCillis5, T. Tamura6
  • 1Division Of Thoracic Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 2Division Of Thoracic Oncology, National Cancer Center Hospital, Tokyo/JP
  • 3Medical Oncology, National Cancer Center Hospital, JP-104-0045 - Tokyo/JP
  • 4Medical Affairs, Exelixis, Inc., South San Francisco/US
  • 5Clinical Development And Medical Affairs, Exelixis, Inc., 94083 - South San Francisco/US
  • 6Division Of Internal Medicine And Thoracic Oncology, National Cancer Center Hospital, Tokyo/JP

Abstract

Background

Cabozantinib is a potent targeted therapy that inhibits MET, VEGFR2, and RET. Anti-tumor activity in patients (pts) has been observed in a broad range of tumors including NSCLC. The primary objective of this phase 1 study is to determine the maximum tolerated dose (MTD) / recommended phase 2 dose in Japanese pts.

Methods

Pts with advanced solid malignancies are enrolled in successive cohorts to receive escalating doses of cabozantinib orally once daily in a 3 + 3 trial design. Dose limiting toxicities (DLTs) are determined using Cycle 1 data. Response is assessed using modified RECIST v1.0. Results: As of 1 June 2012, 14 pts were enrolled including 5 pts with non-small cell lung adenocarcinoma. Pts have been treated at 3 dose levels: 40, 60 and 80 mg. The NSCLC pts had a median of 4 prior regimens (range, 2 – 6). Four of the 5 NSCLC pts had a confirmed partial response (cPR) including a 51 yo female whose pre-treatment tumor sample lacked an EGFR activating mutation Analysis of tumor obtained pre-treatment and at progression demonstrated a KIF5B-RET fusion.

Age Gender Smoking History Molecular Profile Treatment Duration (mos) Best Response
64 Female Never EGFR mutation 15+ cPR
51 Female Former EGFR wt, RET fusion positive 9 cPR
58 Female Never EGFR wt 10 cPR
43 Male Former ALK fusion positive 4 cPR
64 Female Never EGFR wt, ALK fusion negative 6.5 SD

DLT of Grade 3 hypertension was reported in 2 pts. The MTD using a capsule formulation is 60 mg. Adverse events were generally mild to moderate and include hypertension, palmar-plantar erythrodysesthesia, diarrhea, mucositis, rash, edema and headache. Laboratory abnormalities include elevated AST/ALT, lipase and TSH; and neutropenia and thrombocytopenia. Preliminary PK analysis showed that dose-normalized exposure in Japanese pts is approximately 2-fold higher than in non-Japanese pts. Despite relatively higher exposures, cabozantinib 60 mg daily appears to be a well tolerated dose. Conclusions: Cabozantinib appears well tolerated. Signs of antitumor activity include response and prolonged stable disease in NSCLC pts. Accrual and additional molecular characterization is ongoing.

Disclosure

H. Nokihara: Taiho Pharmaceutical Co., Ltd, Merck Serono, Pfizer. N. Yamamoto: Chugai pharmaceutical co., ltd., Pfizer, Kyowa-Hakko Kirin co., ltd. Y. Yamada: Bayer, Yakult, AstraZeneca. J. Frye: Paid employee of Exelixis Exelixis stock ownership. A. Decillis: Paid Employee of Exelixis Exelixis Stock Ownership. T. Tamura: Chugai Pharmaceutical co., ltd., Daichi-Sankyo co., ltd., Boehringer Ingelheim, Abbott Japan Co., Ltd, Eisai co., ltd., Bristol-Myers Squibb, Kyowa-Hakko Kirin co., ltd. All other authors have declared no conflicts of interest.