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Cancer Chemother Pharmacol. 2017 May;79(5):923-932. doi: 10.1007/s00280-017-3283-z. Epub 2017 Mar 28.

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

Author information

1
Stanford Cancer Institute, 875 Blake Wilbur Drive, Rm 2233, Stanford, CA, 94305-5826, USA. hwakelee@stanford.edu.
2
Yale University Cancer Center, New Haven, CT, USA.
3
Massachusetts General Hospital, Charlestown, MA, USA.
4
Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
5
Swedish Cancer Institute, Seattle, WA, USA.
6
Department of Hematology and Oncology, Georgetown University Hospital, Washington, DC, USA.
7
Park Nicollet Cancer Center, Minneapolis, MN, USA.
8
Summit Medical Group, Berkeley Heights, NJ, USA.
9
Exelixis, South San Francisco, CA, USA.
10
University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.

Abstract

PURPOSE:

Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.

METHODS:

This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).

RESULTS:

Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.

CONCLUSIONS:

Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.

KEYWORDS:

Cabozantinib; Combination therapy; Erlotinib; Non-small cell lung cancer; Phase Ib/II; Resistance

PMID:
28352985
PMCID:
PMC5403837
DOI:
10.1007/s00280-017-3283-z
[Indexed for MEDLINE]
Free PMC Article

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