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

Heather A. Wakelee, Scott Gettinger, Jeffrey Engelman, Pasi A. Jänne, Howard West, Deepa S. Subramaniam, Joseph Leach, Michael Wax, Yifah Yaron, Dale R. Miles, Primo N Lara

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalCancer Chemotherapy and Pharmacology
DOIs
StateAccepted/In press - Mar 28 2017

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Non-Small Cell Lung Carcinoma
Cells
Pharmacokinetics
Maximum Tolerated Dose
cabozantinib
Erlotinib Hydrochloride
Pharmacodynamics
Toxicity
Diarrhea
Phosphotransferases
Safety

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. / Wakelee, Heather A.; Gettinger, Scott; Engelman, Jeffrey; Jänne, Pasi A.; West, Howard; Subramaniam, Deepa S.; Leach, Joseph; Wax, Michael; Yaron, Yifah; Miles, Dale R.; Lara, Primo N.

In: Cancer Chemotherapy and Pharmacology, 28.03.2017, p. 1-10.

Research output: Contribution to journalArticle

Wakelee, HA, Gettinger, S, Engelman, J, Jänne, PA, West, H, Subramaniam, DS, Leach, J, Wax, M, Yaron, Y, Miles, DR & Lara, PN 2017, 'A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer', Cancer Chemotherapy and Pharmacology, pp. 1-10. https://doi.org/10.1007/s00280-017-3283-z
Wakelee, Heather A. ; Gettinger, Scott ; Engelman, Jeffrey ; Jänne, Pasi A. ; West, Howard ; Subramaniam, Deepa S. ; Leach, Joseph ; Wax, Michael ; Yaron, Yifah ; Miles, Dale R. ; Lara, Primo N. / A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. In: Cancer Chemotherapy and Pharmacology. 2017 ; pp. 1-10.
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AU - Wakelee, Heather A.

AU - Gettinger, Scott

AU - Engelman, Jeffrey

AU - Jänne, Pasi A.

AU - West, Howard

AU - Subramaniam, Deepa S.

AU - Leach, Joseph

AU - Wax, Michael

AU - Yaron, Yifah

AU - Miles, Dale R.

AU - Lara, Primo N

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N2 - 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.

AB - 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.

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KW - Combination therapy

KW - Erlotinib

KW - Non-small cell lung cancer

KW - Phase Ib/II

KW - Resistance

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