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A. Mita
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.08 - NOTCH3 Protein Expression and Outcome in Small Cell Lung Cancer (SCLC) and Therapeutic Targeting with Tarextumab (Anti-Notch 2/3) (ID 2999)
17:25 - 17:30 | Author(s): A. Mita
- Abstract
- Presentation
Background:
NOTCH expression is associated with cancer cell survival via effects on cancer stem/progenitor cells. Targeting NOTCH2 and 3 decreases growth and survival of SCLC patient-derived human tumor xenografts (PDX). Phase1b/2 trials testing Tarextumab (TRXT) anti-NOTCH2/3 therapy are underway (NCT01647828 and NCT01859741) and show promising anti-tumor activity. Here, we studied NOTCH3 protein expression using immunohistochemistry (IHC) in SCLC human tissues and correlated with survival. Also, we studied NOTCH3 gene expression in phase 1b patients (pts) treated with TRXT.
Methods:
For NOTCH IHC staining, murine monoclonal antibodies were generated by immunizing mice with a NOTCH3 extracellular domain (ECD) protein, then creating hybridomas. Clones were screened by FACS and western blots for specificity to NOTCH3.ECD. A lead clone was selected for NOTCH3 protein measurement in 47 SCLC samples represented in a tissue microarray from Yale Pathology Tissue Services (YPTS). NOTCH3 signal was determined in tumors using H-scores generated by Leica Aperio Scanscope IHC membrane image analysis. For survival analysis, NOTCH3 signal was binarized with cutoffs defined by X-tile software. For the phase 1b clinical trial, a standard 3+3 dose escalation design was employed with cohorts of 3 to 6 pts treated at each dose level. TRXT was given IV on Day 1 of each 21 day cycle with etoposide 100 mg/m[2] (Days 1-3) and cisplatin 80 mg/m[2 ]or carboplatin at AUC 5 (Day 1) for 6 cycles, followed by TRXT alone every 21 days until progression of disease or unacceptable toxicities. Then, the MTD TRXT plus etoposide and carboplatin was confirmed in a cohort of 6 subjects. All pts are required to submit tissues for Notch 3 gene expression and IHC staining.
Results:
A single hybridoma clone demonstrating specific reproducible membranous staining with a dynamic range for NOTCH3.ECD in control and PDX tissues was chosen for IHC analysis in SCLC human FFPE tissues (n=47). Forty cases (85.1%) demonstrated NOTCH3 signal, with eighteen (38.3%) having none to very low signal. Of the 31 cases with adequate follow-up, there was a strong trend with worse outcome and high NOTCH3 expression in the extensive stage (p=0.063), but not in limited stage (p=0.857). The level of significance was a function of the experimental cut-point and can only be considered exploratory. Finally, 27 pts were treated with TRXT in the phase 1b trial, with an overall response rate of 84%. The median duration of treatment was 128 days (6 cycles) with mPFS and mOS of 124 and 228 days, respectively. The median follow-up for PFS and OS was 86 and 107 days, respectively. Twenty-five pts have tissues evaluable for NOTCH3 gene expression and the analysis is underway.
Conclusion:
NOTCH3 IHC staining showed expression in most SCLC cases, with high NOTCH3 trending towards worse survival in extensive stage. This supports the rationale of targeting NOTCH3 by TXRT in SCLC pts. Further evaluation of the prognostic and predictive value of TRXT for anti-Notch therapies in SCLC is underway in an ongoing Phase 2 clinical trial.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-057 - Randomized Phase 2 Study of Plinabulin and Docetaxel in Patients with Advanced Non-Small Cell Lung Cancer - Mechanism-Based Efficacy Analyses (ID 1505)
09:30 - 09:30 | Author(s): A. Mita
- Abstract
Background:
Plinabulin (N), a tubulin binding agent, which depolarizes microtubules, resulting in tumor vasculature obliteration, apoptosis via JNK pathway and maturation of dendritic cells. A multicenter randomized phase 2 study was performed to compare overall survival (OS) between plinabulin/docetaxel (DN) and docetaxel (D). Results of Intent-to-treat (ITT) analyses have been presented at ASCO 2014. The primary objective of OS prolongation was not met, however, exploratory mechanism based analysis revealed improvement in outcomes in patients with large tumors.
Methods:
From November 2008 to July 2011 172 patients with advanced NSCLC who progressed after at least one chemotherapy were enrolled. Patients were treated with D 75mg/m[2] on day 1 and N 30 mg/[2] on days 1 and 8. A second cohort of N 20 mg/m[2] was also enrolled. This exploratory analysis is based on 105 patients (50 DN arm and 55 D arm) receiving 30 mg/m[2] dose, which was selected for an ongoing Phase 3 study and explains the population chosen for future investigation.
Results:
Median OS was 8.7 months (m) (CI 6.6-12.6) in DN arm and 7.5 m (6.3-10.5) in D arm (p=0.899, HR=0.97). PFS was 2.8 m and 3.5 m and ORR was 14.0% vs 14.5% respectively. Among clinical parameters, lesion size (Table 1) and presence of pulmonary disease were identified to impact OS. The OS in patients with pulmonary disease was 11.3 m (6.7-15.1) in DN and 6.7 m (6-9.8) in D, respectively (p=0.29, HR=0.76) regardless of lesion size. Table 1: Exploratory Analysis of Overall Survival by Tumor Size
CI = confidence interval; D = docetaxel; DN, docetaxel + plinabulin; ITT = intent-to-treat; OS = overall survival (Months).Patients Tumor size Median OS Months (95% CI) Hazard Ratio P-value DN (30mg/m[2]) D ITT 1 and 2 prior chemo-therapy All 8.68 (6.33, 12.63) N=50 7.47 (6.17, 10.60) N=55 0.972 0.8993 ≤ 3 cm 6.45 (3.73, NA) N=16 6.47 (5.6, 22.43) N=19 0.934 0.8687 > 3 cm 8.98 (6.60, 12.63) N=34 7.47 (4.77, 11.60) N=36 0.967 0.8990 > 5 cm 8.98 (4.57, 19.23) N= 20 6.70 (4.07, 12.93) N=21 0.750 0.4176 > 7 cm 7.32 (4.57, 19.23) N= 8 5.03 (2.93, 6.70) N= 10 0.507 0.1936
Conclusion:
Mechanism-based exploratory analyses of Phase 2 results have identified advanced NSCLC patients with lung lesion size >3 cm to have benefited from plinabulin. A Phase 3 to confirm this observation is on-going.
