PurposeMalignant pleural mesothelioma (MPM) is a rare malignancy with a dismal median survival of <12 months with current therapy. Single and combination chemotherapy regimens have shown only modest clinical benefit. In preclinical studies, nitrogen-containing bisphosphonates (zoledronic acid) inhibit growth of mesothelioma cells by different mechanisms: inhibition of mevalonate pathway, inhibition of angiogenesis, activation of apoptosis through caspase activation, and alteration in activity of matrix metalloproteinases, thereby affecting invasiveness of cancer cells.Patients and methodsWe investigated the role of zoledronic acid in a pilot, single-arm trial of MPM patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2 who had progressed on prior treatments or had not received systemic therapy due to poor PS. Primary end point was composite response rate by modified response evaluation criteria in solid tumors and/or metabolic response by 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG) positron emission tomography criteria. Secondary end points were progression-free survival (PFS) and overall survival (OS). Exploratory end points include the effect of zoledronic acid therapy on vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 8, transforming growth factor beta, mesothelin, and osteopontin levels.ResultsEight male patients (median age of 62 years) with the following clinical characteristics were treated; ECOG PS was 0–2, 75% with epithelioid type, and 62% had prior chemotherapy Overall composite response rate was 12.5% and the clinical benefit rate (response + stable disease) was 37.5%. Median PFS was 2 months (0.5–21 months) and median OS was 7 months (0.8–28 months). No treatment-related toxicities were observed. Lower VEGF levels were predictive of favorable response and mesothelin levels correlated with disease course.ConclusionZoledronic acid shows modest clinical activity without significant toxicity in patients with advanced MPM.
Purpose Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The primary objective of this first in-human study was to evaluate the safety and tolerability of nintedanib in combination with bevacizumab. Methods Patients were treated with escalating doses of nintedanib (150mg or 200mg oral twice daily) and bevacizumab (15 mg/kg once intravenously every 3weeks) until disease progression or unacceptable toxicity using standard 3 + 3 phase1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes. Results Eighteen patients with advanced tumors (lung (n=9), colon (n=8), and cervical (n=1)) previously treated with at least two lines of chemotherapy including bevacizumab (n=9, 50%) were enrolled. The highest dose of nintedanib was 200mg twice a day with no observed dose limiting toxicities (DLT). Common adverse events (AE) were fatigue (grade 1–3) and diarrhea (grade 1–2). Durable clinical response was observed in 55% patients pre-treated with bevacizumab (1 complete and 4 stable response). Better disease control was correlated with higher than median baseline values for VEFGR2 and E-selectin, and lower levels for SDF-1α. Conclusion Nintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.
Introduction The goal of this study was to explore the efficacy and tolerability of metronomic chemotherapy, a novel anti-angiogenic treatment strategy, in combination with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC) Methods Subjects with newly diagnosed stage IV NSCLC were treated with 4-week cycles of paclitaxel 80 mg/m2 and gemcitabine 300 mg/m2 weekly for three weeks, plus bevacizumab 10 mg/kg every two weeks. Radiologic assessments were performed every 8 weeks. The primary endpoint was progression free survival (PFS). An exploratory objective was to correlate plasma levels of angiogenic biomarkers with treatment response. Results Thirty-nine subjects were included in the intent to treat (ITT) analysis. The objective response rate (ORR) was 56%, the median PFS was 8.5 months, and median overall survival (OS) was 25.5 months. The PFS rate at 6, 12, and 24 months was 61%, 21%, and 11% respectively. The OS rate at 12 and 24 months was 74% and 53% respectively. Treatment was well tolerated, without significant myelosuppressive, gastrointestinal, or neurologic events. Subjects with less than median baseline values of angiopoietin-2 and IL-8 experienced significantly longer PFS. Longer OS was associated with subjects with less than the median baseline values for PLGF and angiopoietin-2. There were statistically significant differences in median values of several biomarkers between cycles 1 and 3 in subjects with objective responses. Conclusions The combination of paclitaxel and gemcitabine, delivered in a metronomic schedule, in combination with bevacizumab, appears to be an effective and tolerable treatment strategy in patients with advanced NSCLC.
8057 Background: Targeting vascular endothelial growth factor (VEGF) has shown modest improvement in pts with adv NS-NSCLC. The incorporation into MC regimens of antiangiogenic agents has been shown to further enhance efficacy in preclinical models. The goal of this pilot study was to achieve a 30% improvement in the 6.4 months (M) progression-free survival (PFS) observed in ECOG 4599. Methods: Untreated pts with stage 4 NS-NSCLC, PS 0-1 and measurable disease were treated with a 4-week (W) cycle of paclitaxel (80mg/m2 D1, 8, 15), gemcitabine (G) (200-300mg/m2 D1, 8, 15) and B (10mg/m2 D1, 15) for 6 cycles. Pts without progressive disease or significant toxicity (Tx) received maintenance B every 2 w. Primary endpoint:PFS. Secondary endpoints: ORR, OS, Tx and biomarker (BM) correlation. Blood samples for angiogenic (VEGF, sVEGFR2, BFGF, PLGF, PDGFα, Ang-2, IL-8, E-Selectin, ICAM-1, TGFβ-1, SDF-1α, endocan) and antiangiogenic (Thrombospondin-1, Ang-1) bm were collected at different intervals in 21 pts. Response assessment (RECIST) was performed every 8 w. Results: 33 evaluable pts were enrolled. Pt characteristics: median age 59 yrs (37-76), 60% female, 70% > 5% weight loss, 24% never/light smokers, 48% genetic testing (mut EGFR-4; ALK(+)-1), and 9% brain mets. Efficacy parameters are shown in the table. 24 pts had an OR (CR-1, PR-23) and 6 pts had stable disease. No significant differences were observed in the efficacy parameters between former smokers vs. never/light smokers. Worst hematologic and non-hematologic Tx: gr 3 neutropenia (N=1); gr 3/4 nausea/vomiting (N=1); gr 3/4 fatigue (N=2); ischemic colitis (N=1); cerebral ischemia (N=1); gr 3/4 pneumonitis [related to G] (N=2); gr 3/4 proteinuria (N=3), and no gr 3/4 hypertension. Conclusions: While conclusions are limited by the size of the trial, the results are consistent with the hypothesis that the addition of B to MC may result in enhanced anti-angiogenic effect and clinical benefits in adv NS-NSCLC. Analysis of prognostic or predictive bm of angiogenesis will be presented. Clinical trial information: NCT00655850. [Table: see text]
B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.
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