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D. Miley



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    P1.13 - Poster Session 1 - SCLC (ID 200)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.13-006 - Phase I/IIa study of the novel combination of bendamustine plus irinotecan followed by etoposide plus carboplatin in untreated patients with extensive stage small cell lung cancer (ID 2567)

      09:30 - 09:30  |  Author(s): D. Miley

      • Abstract

      Background
      Standard therapy for extensive stage small cell lung cancer (ES-SCLC) with etoposide (VP16) plus cisplatin or carboplatin (Carbo) results in median time to progression (TTP) of 4 months with overall survival (OS) of 9 months. Bendamustine (B) induced DNA damage is repaired by excision repair and irinotecan (I), a topoisomerase-1 inhibitor (Top-1), leads to increases in topoisomerase-2 (Top-2), the target of VP16. Therefore, the sequence B+I → VP16+Carbo was hypothesized to increase TTP by exploiting mitotic catastrophe, with subjects with low ERCC-1 expression and high Top-1 or Top-2 expression having longer TTP and OS compared to those with high ERCC-1 expression

      Methods
      This is an open label trial enrolling patients (pts) with evaluable ES-SCLC. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of B+I; the phase IIa primary endpoint was TTP after B+I→E+C. Secondary endpoints were objective response rate (ORR) and OS. In the phase I (N=15), pts received I (150 mg/m[2], d 1) with B at 80, 100, or 120 mg/m[2]/day (d 1,2) every 3 weeks for 3 cycles. Phase IIa pts were treated at the selected phase II dose of B+I for 3 cycles, followed by E (100 mg/m[2], d 1-3) + Carbo (AUC 6, d 1) for 3 cycles. Restaging was performed after 3 cycles of each regimen. The phase IIa was powered to detect a 30% increase in TTP from 4 to 5.2 m with a of 0.1. The Kaplan-Meier method was used to calculate TTP and OS. Toxicities were evaluated using the NCI CTCAE.

      Results
      The MTD of B was not reached and a dose of 100 mg/m[2 ]was selected as the phase IIa dose, with dose-escalation allowed in subsequent cycles of therapy for ≤ grade 2 toxicity. Dose limiting toxicities were diarrhea, nausea, and vomiting. Two treatment-related deaths, from metabolic encephalopathy and from neutropenic sepsis, occurred in the Phase IIa portion. The commonest grade 3/4 hematologic toxicity was neutropenia. Fatigue, nausea, vomiting, and diarrhea were common non-hematologic toxicities. Efficacy Parameters (N=28): Median TTP 6.0 m (95% CI 4.8-7.2); Median OS 10.0 m (95% CI 8.4-11.6); ORR 83% (4% CR); Median tumor reduction after B+I 65%; Median tumor reduction after E+C 73%. Statistically significant prognostic factors for TTP were sex, LDH, Top-1 and Top-2 and for OS were Top-2 and LDH. The predictive significance of Top-1 for TTP is confounded by insufficient samples with no expression of Top-1 and failure to demonstrate correlation with ERCC1 levels may have been related to antibody selection – reanalysis in in progress.

      Conclusion
      B+I is an active regimen in ES-SCLC and the treatment sequence B+I→E+C seems to improve the TTP and OS in ES-SCLC compared to historic results for E+C. Toxicities were increased compared to historic results for E+C, but were manageable. Correlative studies with pre-treatment assessment of tumor ERCC-1 and Top-2 as predictors of response are ongoing.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-008 - Phase II study of metronomic chemotherapy (MC) with bevacizumab (B) in patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC) (ID 898)

      09:30 - 09:30  |  Author(s): D. Miley

      • Abstract

      Background
      Platinum-based chemotherapy regimens using maximum-tolerated dosing schedules are the standard of first-line treatment for advanced non-small cell lung cancer (NSCLC) and are associated with a modest survival benefit and substantial toxicity. Targeting vascular endothelial growth factor (VEGF) has shown modest improvement in patients with advanced NS-NSCLC. Frequent administration of low dose chemotherapy agents (metronomic chemotherapy [MC]) is thought to target endothelial cells of the tumor vasculature as well as tumor cells. The hypothesis of this pilot phase 2 study is that the combination of bevacizumab and MC will result in enhanced antiangiogenic effect and clinical benefit in advanced NSCLC.

      Methods
      Untreated patients with stage 4 non-squamous NSCLC, PS 0-1 and measurable disease were treated with a 4-week cycle of paclitaxel (80 mg/m[2] D1, 8, 15), gemcitabine (200-300 mg/m[2] D1, 8, 15) and bevacizumab (10 mg/kg D1, 15) for 6 cycles. Patients without progressive disease received maintenance bevacizumab every 2 weeks. Primary endpoint: progression-free survival (PFS) with the goal to achieve a 30% improvement in the 6.4 months PFS observed in ECOG 4599. Secondary endpoints: objective response rate (ORR), overall survival (OS), safety, and the evaluation of potential biomarkers of angiogenesis. Blood samples for angiogenic and antiangiogenic biomarkers were collected at different intervals.

      Results
      33 evaluable patients were enrolled. Patient characteristics: median age 59 years; 61% female; 70% ≥5% weight loss; 24% never/light smoker; 48% genetic testing (mut EGFR-4 patients and 1 patient ALK+); and 9% brain metastases. Efficacy parameters are shown in the table below. Worst hematologic and non-hematologic toxicities: grade 3 neutropenia (15%); grade 3 fatigue (6%); grade 3 nausea (3%); grade 3/4 hypertension (30%); grade 3/4 proteinuria (18%); pneumonitis (3 patients); and ischemic events (2 patients). The following baseline biomarkers have shown significant correlation with response parameters: (VEGF2 (ORR); PLGF (OS); angiopoietin -2 (PFS, OS); endocan (ORR); IL-8 (ORR, PFS); TGFβ-1 (ORR); thrombospondin-1 (ORR); and angiopoietin-1(ORR).

      Clinical Results
      Patients (N=33)
      PFS (mo)
      Median 9 (95% CI:7; 10)
      OS (mo)
      Median 30 (95% CI: 18; 37)
      1-year survival rate 74%
      2-year survival rate 55%
      ORR 73% (95% CI:0.54; 0.87)
      CR N=1
      PR N=23
      Stable Disease N=6 (18%)
      Progressive Disease N=3 (9%)
      Never or Light Smokers N=8
      Median PFS : 10m
      Median OS : 37m

      Conclusion
      MC with a platinum doublet in combination with bevacizumab is a feasible, tolerable, and active regimen in advanced non-squamous NSCLC. Potential biomarkers were correlated with clinical outcome.