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R. Jotte
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.07 - Clinical Attributes of Lung Cancer in US Community Oncology Practice: Implications for Immunotherapy (ID 733)
17:20 - 17:25 | Author(s): R. Jotte
- Abstract
- Presentation
Background:
The majority of lung cancer in the US is treated in the community. A prospective cohort study of stage IV non-small cell lung cancer (NSCLC) and extensive disease small cell lung cancer (ED SCLC) is being conducted in 70 US community oncology practices (Figure) to assess current standards of care (SOC) and outcomes in anticipation of immunotherapy as a new treatment modality. This study establishes a historical comparator cohort in a “pre-immunotherapy era” of lung cancer treatment. Figure 1
Methods:
Patients with stage IV NSCLC and ED SCLC, at any point in their care, with documented dates of diagnosis and prior treatment, are eligible for inclusion. Patients are followed prospectively for 36 months or until death, with data abstraction from medical records into electronic case report forms. Patient-reported outcomes are prospectively collected, as are archival tumor tissue and serial blood samples from consenting patients for molecular profiling studies.
Results:
This early analysis focused on patient clinical attributes and tumor sample characteristics of relevance to non-clinical trial patient populations and to biomarker testing (Table). Of 1,183 cases enrolled to date, at enrollment 17.6% were ECOG performance status (PS) 2 or 3, 18.8% of patients had brain metastases, 22.2% were on systemic steroids, 6.7% had history of a specific autoimmune condition, and 49.5% had had tissue samples from core needle or surgical specimens.Figure 1
Conclusion:
Many immunotherapy clinical trials exclude patients with brain metastases, certain steroid use, poor PS, and autoimmune disease, yet a substantial proportion of community-based lung cancer patients present with these attributes. Approximately half of advanced stage patients have tissue specimens amenable to current SOC biomarker testing. Efforts to develop additional biomarker tests for lung cancer patients need to consider the reality of limited tissue sample availability in the community setting.
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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): R. Jotte
- 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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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.02 - Safety and Efficacy of Nivolumab in an Ongoing Trial of a PD-L1+/- Patient Population with Metastatic Non-Small Cell Lung Cancer (ID 851)
10:56 - 11:07 | Author(s): R. Jotte
- Abstract
- Presentation
Background:
Nivolumab (NIVO), a fully human IgG4 programmed death-1 (PD-1), immune checkpoint inhibitor antibody, has demonstrated durable responses and tolerability in heavily pretreated patients with advanced non-small cell lung cancer (NSCLC). NIVO was recently approved for the treatment of patients with metastatic squamous (SQ) NSCLC with progression on or after platinum-based chemotherapy. Conducted mostly in community-based oncology centers, this ongoing trial explores the safety of NIVO in patients with previously-treated PD-L1[+/-] metastatic SQ or non-squamous (NSQ) NSCLC.
Methods:
Eligible patients are enrolled in 4 subgroups: 1) SQ, performance status (PS) 0–1, ≥2 prior therapies; 2) SQ, PS 0–1, 1 prior therapy; 3) NSQ, PS 0–1, ≥1 prior therapy; and 4) SQ or NSQ, PS 2, ≥1 prior therapy. Patients with both PD-L1[+] and PD-L1[-] tumors are eligible. Patients receive NIVO 3 mg/kg IV (60 minutes) Q2W either until progressive disease (PD)/unacceptable toxicity (Cohort A) or for 1 year with the possibility of retreatment upon disease progression (Cohort B). Primary objective is to estimate incidence of high-grade (CTCAE v4.0 Grade 3–4 and 5), select treatment-related adverse events (STRAEs); exploratory efficacy assessments include ORR, PFS, and OS.
Results:
From 4/16/14 to 12/31/14, 824 patients were treated and have demographic and safety data available; 483 patients remained on study as of 12/31/2014. 395 patients had evaluable radiographic tumor assessments at first assessment (Week 9). Demographics, safety, and tumor response by PD-L1 status are reported. Figure 1
Conclusion:
Safety and tolerability are consistent with prior NIVO experience and no new safety signals have been identified in this trial of SQ/NSQ NSCLC patients. Immune-related toxicities are manageable in a community practice setting using previously-developed safety algorithms. The frequency of STRAEs of interest was similar between patients with PS 0–1 and those with PS 2. Early data from this large, multicenter trial suggests that patients with pretreated advanced NSCLC benefit from NIVO therapy regardless of tumor PD-L1 status, histology type, and PS status.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-099 - nab-Paclitaxel as Maintenance Therapy in Patients with Squamous Cell NSCLC (ABOUND.sqm) (ID 3122)
09:30 - 09:30 | Author(s): R. Jotte
- Abstract
Background:
Patients with squamous cell (SCC) non-small cell lung cancer (NSCLC) may be at risk of poorer outcomes and have fewer treatment options than those with other histologies. Furthermore, no randomized studies have demonstrated the benefit of maintenance therapy in these patients. In a phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) demonstrated a 68% improvement in the overall response rate (ORR; 41% vs 24%; P < 0.001) and a trend toward improved overall survival (OS; median, 10.7 vs 9.5 months; HR 0.890; P = 0.310) compared with solvent-based paclitaxel plus C in a subset of patients with advanced SCC NSCLC (Socinski et al. Ann Oncol. 2013;24:2390-2396). An exploratory analysis of the phase III trial demonstrated that therapy with nab-P/C beyond 4 cycles of first-line treatment was effective in the subset of patients with SCC NSCLC who did not progress (from the time of randomization, median progression-free survival [PFS] and OS were 6.8 and 13.8 months, respectively), and no new safety signals were noted (Socinski et al. IASLC 2013 [abstract 3438]). In the open-label, multicenter phase III ABOUND.sqm trial, the efficacy and safety of nab-P maintenance therapy after nab-P/C induction therapy will be evaluated in patients with advanced SCC NSCLC.
Methods:
During the induction part of the study, approximately 540 patients will be treated with 4 cycles of nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1, 8, and 15 plus IV C AUC 6 on day 1 every 21 days. Patients with a complete response (CR), a partial response (PR), or stable disease (SD) will be eligible for maintenance. In the maintenance part of the study, approximately 260 patients will be randomized 2:1 to nab-P 100 mg/m[2] on days 1 and 8 every 21 days plus best supportive care (BSC) or BSC alone until disease progression. Patients will be stratified by disease stage (IIIB vs IV), response to induction therapy (CR/PR vs SD), and ECOG performance status at the end of induction (0 vs 1). Key eligibility criteria include histologically or cytologically confirmed stage IIIB/IV SCC NSCLC, no prior chemotherapy for metastatic disease, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, and preexisting peripheral neuropathy grade < 2. ClinicalTrials.gov identifier NCT02027428.Key Endpoints Primary PFS from randomization into the maintenance part of the study Secondary Safety OS from randomization into the maintenance part of the study ORR during the induction and maintenance parts of the study Exploratory Correlation between pretreatment tumor characteristics and response to treatment Association between changes in tumor characteristics and acquisition of resistance to therapy at the time of treatment failure during maintenance Correlation between genetic polymorphisms and treatment efficacy and/or toxicity Healthcare resource utilization during the maintenance part of the study Changes in quality of life
Results:
Not applicable.
Conclusion:
Not applicable.
