RESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/sangue , Carboplatina/farmacologia , Etoposídeo/farmacologia , Células Neoplásicas Circulantes , Peptídeos Cíclicos/farmacologia , Receptores CXCR4/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Contagem de Células , Intervalo Livre de Doença , Etoposídeo/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Peptídeos Cíclicos/uso terapêutico , Prognóstico , Receptores CXCR4/metabolismo , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/metabolismoRESUMO
OBJECTIVES: This multicenter, open-label, randomized phase II study evaluated the efficacy and safety of LY2510924 (LY) added to first-line standard of care (SOC) chemotherapy for extensive-disease small cell lung cancer (ED-SCLC) and explored the predictive value of C-X-C motif receptor 4 (CXCR4) tumor response. MATERIALS AND METHODS: Patients with treatment-naïve ED-SCLC were randomized (1:1) to receive up to six 21-day cycles of carboplatin/etoposide alone (SOC) or in combination with 20mg LY2510924 administered subcutaneously on days 1-7 of each cycle (LY+SOC). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Response relative to CXCR4 expression on baseline tumor was an exploratory endpoint. RESULTS: Of 94 patients randomized, 90 received treatment (LY+SOC, n=47; SOC, n=43). Median PFS (95% confidence interval [CI]) was 5.88 (4.83, 6.24) months for LY+SOC versus 5.85 (4.63, 5.51) months for SOC (hazard ratio [95% CI], 1.01 [0.62, 1.63]; p=0.9806). Median OS (95% CI) was 9.72 (6.64, 11.70) months for LY+SOC versus 11.14 (8.25, 13.44) months for SOC. ORR was 74.5% for LY+SOC versus 81% for SOC. Safety results between arms were similar, although the following adverse events were more frequent on the LY+SOC arm: anemia (61.7% vs 46.5%), neutropenia (61.7% vs 53.5%), leukopenia (27.7% vs 9.3%), vomiting (27.7% vs 16.3%), and pneumonia (10.6% vs 2.3%). In patients whose baseline CXCR4 expression was above the optimal cutoff (H-score 210), the hazard ratio (95% CI) was 1.27 (0.51, 3.15). CONCLUSION: LY2510924 did not improve efficacy but had an acceptable toxicity profile when added to SOC for ED-SCLC.