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P.J. Loehrer, Sr.
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OA18 - New Insights in the Treatment of Thymic Malignancies (ID 408)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:N. Girard, S.B. Watzka
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 2
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OA18.02 - Evaluation of a Modified Dosing Regimen (2-Weeks on/1-Week off) of Sunitinib as Part of a Phase II Trial in Thymic Carcinoma (ID 6289)
11:10 - 11:20 | Author(s): P.J. Loehrer, Sr.
- Abstract
- Presentation
Background:
Sunitinib is active in patients with recurrent thymic carcinoma (TC). We have previously reported an objective response rate of 26% and disease control rate (partial response and stable disease) of 91% in patients with TC when sunitinib is administered at a dose of 50 mg once daily for 4 weeks followed by 2 weeks off (4/2 dosing schedule). Grade 3 or 4 treatment-related adverse events (TEAEs) occurring in more than 10% of patients included fatigue, oral mucositis and lymphocytopenia (20% each), and hypertension (13%). Grade 3 decrease in left ventricular ejection fraction (LVEF) was observed in 8% of patients. Alternative dosing schedules have been evaluated in solid tumors to improve tolerability. As part of an ongoing phase II study (NCT01621568), we evaluated the clinical activity and tolerability of sunitinib in patients with TC using a 2-weeks-on/1-week-off (2/1) dosing regimen.
Methods:
Patients with progressive TC after at least one prior platinum-containing chemotherapy regimen, measurable disease, and adequate end organ function were enrolled and received sunitinib at a dose of 50 mg orally once daily using a 2/1 schedule until disease progression or development of intolerable adverse events. The primary objective was evaluation of response rate. Tumor assessments were performed every 6 weeks using RECIST version 1.1 and toxicity was assessed every 3 weeks using CTCAE version 4.0. Exploratory correlative studies including evaluation of immune cell subsets will be reported separately.
Results:
Between July 8, 2014 and January 14, 2016, 15 patients were enrolled. Median age was 62 years (range, 41-76), and 33% were male. A median of 4 (range, 1 – 33+) cycles of sunitinib was administered. Among 13 evaluable patients, there was 1 (8%) partial response, 11 (85%) stable disease and 1 (8%) progressive disease. After a median follow-up of 16 months, the median progression-free survival was 5 months and median overall survival was 16 months. Grade 3 or 4 TEAEs occurring in more than 10% of patients included lymphocytopenia (40%), neutropenia and leucopenia (20% each), thrombocytopenia and oral mucositis (13% each). Grade 3 decrease in LVEF was observed in 1 (7%) patient.
Conclusion:
Sunitinib, administered using a 2/1 dosing schedule, has clinical activity in patients with TC, and the frequency of clinically significant TEAEs (fatigue, mucositis, hypertension) is acceptable. Studies are ongoing to identify novel immunological biomarkers of activity.
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P2.04 - Poster Session with Presenters Present (ID 466)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.04-019 - A Peripheral Immune Signature Associated with Clinical Activity of Sunitinib in Thymic Carcinoma (ID 6184)
14:30 - 14:30 | Author(s): P.J. Loehrer, Sr.
- Abstract
Background:
We have previously reported an objective response rate of 26% and disease stabilization in 65% of patients with advanced thymic carcinoma (TC) treated with the multikinase inhibitor sunitinib after failure of platinum-based chemotherapy. The current study investigates the impact of sunitinib on systemic immunity in patients with thymic epithelial tumors with an aim to discover blood-based, predictive immune biomarkers.
Methods:
Patients with thymoma and TC received sunitinib at a dose of 50 mg once daily in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment. Results from 15 patients with TC are reported here. Blood samples were collected before initiation of sunitinib therapy (Cycle 1 day 1; C1D1), and prior to treatment on day 1 of cycles 2 and 3 (C2D1; C3D1). Multiparameter flow cytometry was used to study T-cell subsets with immune checkpoint expression, four phenotypes of myeloid-derived suppressor cells (MDSCs) with CD40, and CD14+ monocytes with HLA-DR expression. Expression of 730 immune-related genes in peripheral blood was analyzed by NanoString technology. Differences in paired markers or changes in markers between two time points was evaluated by the Wilcoxon signed rank test. The Kaplan-Meier method was used to obtain estimates of progression-free survival (PFS) and overall survival (OS).
Results:
Immunosuppressive Tim-3-positive Tregs declined after 2 cycles of sunitinib (p=0.024). A decrease in granulocytic MDSCs (p=0.012), lineage negative (CD3-CD19-CD56-) MDSCs (p=0.013), and immature MDSCs (p=0.01) but not monocytic MDSCs was observed after 1 cycle of sunitinib. TC patients with no objective response to sunitinib had a higher baseline immature MDSC level than responders (p=0.0044). Greater than median declines in granulocytic MDSC CD40 (C2D1 p=0.027, C3D1 p=0.0046) and lineage-MDSC CD40 (C3D1, p=0.0046) after sunitinib therapy was associated with improved PFS. Similarly, a greater than median decline in CD14[+]HLA-DR[lo/neg ]monocyte levels on C2D1 was associated with longer PFS (p=0.020). Among the immune genes examined, higher baseline FEZ1 expression was associated with improved PFS and OS.
Conclusion:
Our findings suggest significant interplay between sunitinib and systemic immunity impacts therapeutic outcome in TC. Monitoring CD40 expression on specific MDSC phenotypes and FEZ1 gene expression may predict a survival benefit after treatment with sunitinib. These results, if validated in larger studies, can serve as potential blood-based predictive biomarkers in TC patients treated with sunitinib.
