Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial

Raya Leibowitz-Amit, Melania Pintilie, Leila Khoja, Arun A Azad, Raanan Berger, A Douglas Laird, Dana T Aftab, Kim N Chi, Anthony Joshua Cardin

Research output: Contribution to journalArticleResearchpeer-review

Abstract

BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 ) and 6/33 pts (18 ) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.
Original languageEnglish
Article number12
Number of pages8
JournalJournal of Translational Medicine
Volume14
Issue number1
DOIs
Publication statusPublished - 13 Jan 2016
Externally publishedYes

Keywords

  • Prostate cancer
  • Cabozantinib
  • Biomarker
  • c-MET
  • VEFR
  • VEGF

Cite this

Leibowitz-Amit, Raya ; Pintilie, Melania ; Khoja, Leila ; Azad, Arun A ; Berger, Raanan ; Laird, A Douglas ; Aftab, Dana T ; Chi, Kim N ; Cardin, Anthony Joshua. / Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial. In: Journal of Translational Medicine. 2016 ; Vol. 14, No. 1.
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Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial. / Leibowitz-Amit, Raya; Pintilie, Melania; Khoja, Leila; Azad, Arun A; Berger, Raanan; Laird, A Douglas; Aftab, Dana T; Chi, Kim N; Cardin, Anthony Joshua.

In: Journal of Translational Medicine, Vol. 14, No. 1, 12, 13.01.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial

AU - Leibowitz-Amit, Raya

AU - Pintilie, Melania

AU - Khoja, Leila

AU - Azad, Arun A

AU - Berger, Raanan

AU - Laird, A Douglas

AU - Aftab, Dana T

AU - Chi, Kim N

AU - Cardin, Anthony Joshua

PY - 2016/1/13

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N2 - BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 ) and 6/33 pts (18 ) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.

AB - BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 ) and 6/33 pts (18 ) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.

KW - Prostate cancer

KW - Cabozantinib

KW - Biomarker

KW - c-MET

KW - VEFR

KW - VEGF

U2 - 10.1186/s12967-015-0747-y

DO - 10.1186/s12967-015-0747-y

M3 - Article

VL - 14

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

IS - 1

M1 - 12

ER -