A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors

M. Dror Michaelson, Shilpa Gupta, Neeraj Agarwal, Russell Szmulewitz, Thomas Powles, Roberto Pili, Justine Yang Bruce, Ulka Vaishampayan, James Larkin, Brad Rosbrook, Erjian Wang, Danielle Murphy, Panpan Wang, Maria Josè Lechuga, Olga Valota, Dale R. Shepard

Research output: Contribution to journalArticle

Abstract

Lessons Learned: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy. The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. Background: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. Methods: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. Results: No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9–54.3), and progression-free survival was 5.6 months (95% CI, 3.5–not reached). Conclusion: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

Original languageEnglish (US)
JournalOncologist
DOIs
StatePublished - Jan 1 2019

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Renal Cell Carcinoma
Maximum Tolerated Dose
Neoplasms
Safety
Vascular Endothelial Growth Factor A
Confidence Intervals
Protein-Tyrosine Kinases
Disease-Free Survival
Fatigue
crizotinib
axitinib
Pharmacokinetics
Biomarkers
Neoplasm Metastasis
Hypertension
Therapeutics
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors. / Michaelson, M. Dror; Gupta, Shilpa; Agarwal, Neeraj; Szmulewitz, Russell; Powles, Thomas; Pili, Roberto; Bruce, Justine Yang; Vaishampayan, Ulka; Larkin, James; Rosbrook, Brad; Wang, Erjian; Murphy, Danielle; Wang, Panpan; Lechuga, Maria Josè; Valota, Olga; Shepard, Dale R.

In: Oncologist, 01.01.2019.

Research output: Contribution to journalArticle

Michaelson, MD, Gupta, S, Agarwal, N, Szmulewitz, R, Powles, T, Pili, R, Bruce, JY, Vaishampayan, U, Larkin, J, Rosbrook, B, Wang, E, Murphy, D, Wang, P, Lechuga, MJ, Valota, O & Shepard, DR 2019, 'A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors', Oncologist. https://doi.org/10.1634/theoncologist.2018-0749
Michaelson, M. Dror ; Gupta, Shilpa ; Agarwal, Neeraj ; Szmulewitz, Russell ; Powles, Thomas ; Pili, Roberto ; Bruce, Justine Yang ; Vaishampayan, Ulka ; Larkin, James ; Rosbrook, Brad ; Wang, Erjian ; Murphy, Danielle ; Wang, Panpan ; Lechuga, Maria Josè ; Valota, Olga ; Shepard, Dale R. / A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors. In: Oncologist. 2019.
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abstract = "Lessons Learned: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy. The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. Background: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. Methods: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-na{\"i}ve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. Results: No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2{\%}) and fatigue (9.1{\%}). In the dose-expansion phase, overall response rate was 30{\%} (95{\%} confidence interval [CI], 11.9–54.3), and progression-free survival was 5.6 months (95{\%} CI, 3.5–not reached). Conclusion: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.",
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T1 - A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors

AU - Michaelson, M. Dror

AU - Gupta, Shilpa

AU - Agarwal, Neeraj

AU - Szmulewitz, Russell

AU - Powles, Thomas

AU - Pili, Roberto

AU - Bruce, Justine Yang

AU - Vaishampayan, Ulka

AU - Larkin, James

AU - Rosbrook, Brad

AU - Wang, Erjian

AU - Murphy, Danielle

AU - Wang, Panpan

AU - Lechuga, Maria Josè

AU - Valota, Olga

AU - Shepard, Dale R.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Lessons Learned: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy. The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. Background: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. Methods: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. Results: No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9–54.3), and progression-free survival was 5.6 months (95% CI, 3.5–not reached). Conclusion: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

AB - Lessons Learned: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy. The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. Background: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. Methods: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. Results: No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9–54.3), and progression-free survival was 5.6 months (95% CI, 3.5–not reached). Conclusion: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

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