Abstract
BackgroundIn non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR).MethodsThis single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes.ResultsThirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail.ConclusionsThe combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy.Trial RegistrationClinicalTrials.gov NCT01011075
Highlights
In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR)
Platelet-derived growth factor receptor (PDGFR) and its ligand, PDGF, constitute a tyrosine kinase signaling family involved in angiogenesis, inhibition of apoptosis, and regulation of interstitial fluid pressure (IFP) [1]
We hypothesized that antagonism of PDGFR-β with imatinib could increase the therapeutic index of weekly paclitaxel
Summary
In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). Platelet-derived growth factor receptor (PDGFR) and its ligand, PDGF, constitute a tyrosine kinase signaling family involved in angiogenesis, inhibition of apoptosis, and regulation of interstitial fluid pressure (IFP) [1]. In non-small cell lung cancer (NSCLC) xenografts, imatinib decreased phosphorylated PDGFR-β, vascular endothelial growth factor, and IFP while increasing intratumoral delivery of docetaxel or liposomal doxorubicin [7]. We report the final results from a phase II clinical trial evaluating the combination of weekly paclitaxel and pulse dose imatinib in elderly patients with advanced, chemotherapy-naïve NSCLC
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