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Clinical Trial
. 2017 Jun;35(3):334-344.
doi: 10.1007/s10637-017-0446-z. Epub 2017 Mar 15.

Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study

Ravi Salgia  1 , R Waide Weaver  2 , Michael McCleod  3 , John R Stille  4 , S Betty Yan  5 , Stephanie Roberson  4 , John Polzer  4 , Amy Flynt  6 , Eyas Raddad  4 , Victoria L Peek  5 , Sameera R Wijayawardana  5 , Suzane L Um  5 , Steve Gross  7 , Mark C Connelly  7 , Carrie Morano  7 , Madeline Repollet  7 , Renouard Sanders  7 , Kurt Baeten  8 , David D'Haese  8 , David R Spigel  9
Affiliations
Clinical Trial

Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study

Ravi Salgia et al. Invest New Drugs. 2017 Jun.

Abstract

Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4+ tumor, ≥7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.

Keywords: CXCR4 expression; Carboplatin-etoposide; Circulating tumor cells; LY2510924; Small cell lung cancer.

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Conflict of interest statement

Disclosure of potential conflicts of interest

J.R. Stille, S.B. Yan, S. Roberson, J. Polzer, E. Raddad, V.L. Peek, S.R. Wijayawardana, and S.L. Um are employees and shareholders of Eli Lilly and Company.

S. Gross, M.C. Connelly, C. Morano, M. Repollet, R. Sanders, K. Baeten, and D. D’Haese are employees of Janssen Diagnostics and shareholders of Johnson and Johnson Company.

S. Gross and C. Morano receive royalties from Johnson and Johnson Company.

D.R. Spigel receives no compensation as an advisor to Bristol-Myers Squibb, Genentech/Roche, Novartis, and Pfizer and serves on a data safety monitoring board for Merck.

No conflict of interest was reported by R. Salgia, M. McCleod, R.W. Weaver, or A. Flynt.

Funding

This study was funded by Eli Lilly and Company.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study. The informed consent form was signed by the patient and physician prior to study procedures in accordance with International Conference on Harmonization guidelines on Good Clinical Practice.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves for PFS and OS in the overall patient population by biomarker levels a Baseline CXCR4 expression in tumor tissue H-score ≥ 210 and <210 for PFS; b Baseline CXCR4 expression in tumor tissue H-score ≥ 210 and <210 for OS; c Baseline CTC counts ≥6 and <6 for PFS; d Baseline CTC counts ≥6 and <6 for OS; e Cycle 2, day 1 CTC counts ≥6 and <6 for PFS; f Cycle 2, day 1 CTC counts ≥6 and <6 for OS; g Baseline %CXCR4+ CTCs ≥7% and <7% for PFS; h Baseline %CXCR4+ CTCs ≥7% and <7% for OS; i Cycle 2, day 1 %CXCR4+ CTCs ≥7% and <7% for PFS; j Cycle 2, day 1 %CXCR4+ CTCs ≥7% and <7% for OS
Fig. 1
Fig. 1
Kaplan-Meier curves for PFS and OS in the overall patient population by biomarker levels a Baseline CXCR4 expression in tumor tissue H-score ≥ 210 and <210 for PFS; b Baseline CXCR4 expression in tumor tissue H-score ≥ 210 and <210 for OS; c Baseline CTC counts ≥6 and <6 for PFS; d Baseline CTC counts ≥6 and <6 for OS; e Cycle 2, day 1 CTC counts ≥6 and <6 for PFS; f Cycle 2, day 1 CTC counts ≥6 and <6 for OS; g Baseline %CXCR4+ CTCs ≥7% and <7% for PFS; h Baseline %CXCR4+ CTCs ≥7% and <7% for OS; i Cycle 2, day 1 %CXCR4+ CTCs ≥7% and <7% for PFS; j Cycle 2, day 1 %CXCR4+ CTCs ≥7% and <7% for OS
Fig. 1
Fig. 1
Kaplan-Meier curves for PFS and OS in the overall patient population by biomarker levels a Baseline CXCR4 expression in tumor tissue H-score ≥ 210 and <210 for PFS; b Baseline CXCR4 expression in tumor tissue H-score ≥ 210 and <210 for OS; c Baseline CTC counts ≥6 and <6 for PFS; d Baseline CTC counts ≥6 and <6 for OS; e Cycle 2, day 1 CTC counts ≥6 and <6 for PFS; f Cycle 2, day 1 CTC counts ≥6 and <6 for OS; g Baseline %CXCR4+ CTCs ≥7% and <7% for PFS; h Baseline %CXCR4+ CTCs ≥7% and <7% for OS; i Cycle 2, day 1 %CXCR4+ CTCs ≥7% and <7% for PFS; j Cycle 2, day 1 %CXCR4+ CTCs ≥7% and <7% for OS
Fig. 2
Fig. 2
Kaplan-Meier curves for PFS by treatment arm and biomarker levels. a Baseline ≥6 CTCs; b Baseline ≥7% CXCR4+ CTCs; c Baseline ≥7% CXCR4+ CTCs and ≥6 CTCs. CE carboplatin-etoposide, CI confidence interval, CTCs circulating tumor cells, CXCR4 chemokine (C-X-C motif) receptor 4, HR hazard ratio at 4 months (end of treatment), LY LY2510924, N number of patients, OS overall survival, PFS progression-free survival
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