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MA01 - Oligometastatic Disease (ID 114)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Oligometastatic NSCLC
- Presentations: 1
- Now Available
- Moderators:Anne Marie Clasina Dingemans, Matthias Guckenberger
- Coordinates: 9/08/2019, 10:30 - 12:00, Copenhagen (1980)
MA01.03 - Interim Safety Analysis of the Phase IB Trial of SBRT to All Sites of Oligometastatic NSCLC Combined with Durvalumab and Tremelimumab (Now Available) (ID 2893)
10:30 - 12:00 | Author(s): Jens Eickhoff
Oligometastatic NSCLC represents a unique subset of patients (pts) with limited burden of metastatic disease. Prior early studies have demonstrated that combining local ablative and systemic therapies in pts with oligometastatic disease leads to improved progression-free survival (PFS). The immunostimulatory effects of SBRT and potential synergy with immune checkpoint inhibitors has prompted enthusiasm in combining the two; however, the toxicity is unknown.Method
In this phase Ib study, a cohort of 21 pts with oligometastatic NSCLC receive SBRT to all sites of disease between 30 and 50 Gy in five fractions and durvalumab 1500 mg IV + tremelimumab 75 mg IV every 4 weeks x 4 cycles in a sequential fashion, followed by durvalumab maintenance until progression, unacceptable toxicity or patient wishes. Eligible patients had 1-6 metastatic extracranial lesions, all of which were suitable for SBRT, ECOG performance status 0-1, no actionable driver mutation, and no prior immunotherapy.The primary endpoint is safety of this combination. The period for evaluating dose-limiting toxicities (DLTs) is from the time of first administration of SBRT until 28 days post completion of the first dose of durvalumab and tremelimumab. Grading of DLTs follows CTCAE version 4.03. A DLT will be defined as any Grade≥ 3 toxicity. Secondary endpoints include PFS and overall survival. Correlative studies of baseline TMB, PD-L1 expression on post-SBRT biopsy and immune biomarkers on circulating tumor cells will be correlated with outcomes. In this interim analysis, we assess the safety of the first nine patients enrolled.Result
Nine pts enrolled from 2/2018-3/2019. Median follow-up: 2.8 months (range 1.5-8.2 months). Characteristics included: median age 72 years (range 56-81 years), female/male 2/7, squamous/nonsquamous 2/7, median number of sites treated 2, CNS involvement 3/9. Most toxicities were Grade (G) 1/ 2. Severe adverse events (AEs) included: G4 elevated CK (1). Severe immune-related (ir)AEs: G3 rash (1), G3 AST (2), G3 ALT (1), G3 amylase (1), G3 lipase (1). One DLT reported due to grade 3 AST > 7 days (recovered). One additional pt discontinued treatment due to grade 3 irAE. There were no treatment-related deaths. Two patients (22%) died of disease progression.Conclusion
There were no unexpected safety signals in the first nine patients enrolled. The incidence of grade 3 or greater irAEs was similar to those seen in the treatment of advanced NSCLC, and no additional toxicity is observed with the addition of SBRT to date. The study continues to enroll and results will be updated.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
P1.01-114 - A Phase 2 Study of MLN4924 (Pevonedistat) in Combination with Carboplatin and Paclitaxel in Advanced NSCLC Previously Treated with Immunotherapy (ID 2926)
09:45 - 18:00 | Author(s): Jens Eickhoff
Development of combination strategies after development of resistance to front-line immunotherapy is an area of unmet need in advanced NSCLC. One developing novel therapeutic strategy in NSCLC considers the molecular pathway of the ubiquitin (Ub)/proteasome system (UPS) and is a promising therapeutic target being investigated in hematologic and solid malignancies.
Up-regulation of the neddylation pathway has been shown in NSCLC. In a study evaluating expression of neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) (E1) and NEDD8-conjugating enzyme (E2) expression and global-protein neddylation, both squamous cell and adenocarcinoma NSCLC tumors consistently demonstrated overactivation of the entire neddylation pathway and higher expression of neddylation pathway was associated with poor overall survival (OS).
MLN4924 (pevonedistat) is a first-in-class, small molecule NAE inhibitor. The combination of carboplatin/paclitaxel and MLN4924 (pevonedistat) has been investigated in the phase I setting in multiple solid tumors. Consistent with preclinical studies reporting synergy between MLN4924 (pevonedistat) and platinum-chemotherapy, the objective responses in patients resistant to prior platinum/taxane therapy suggest the potential reversal of resistance by the addition of MLN4924 (pevonedistat).
This is a phase 2, single arm study of MLN4924 (pevonedistat) 20 mg/m2 (Days 1, 3, 5) + carboplatin AUC 5 (Day 1) and paclitaxel 175 mg/m2 (Day 1) every 21 days for at least 4 cycles in patients with advanced NSCLC. At any time after 4 cycles of the combination, pts may continue with a) carboplatin, paclitaxel, and MLN4924 (pevonedistat), or b) continue carboplatin and MLN4924 (pevonedistat) without paclitaxel, or c) observation. Target accrual: 25 patients. Eligible patients have ECOG PS 0-1, measurable disease per RECIST 1.1, progression on prior checkpoint inhibitor and platinum-doublet chemotherapy, and adequate organ function. The primary endpoint is overall response rate (ORR). Secondary endpoints include progression-free survival, OS and safety. Correlative studies include: to evaluate the NQO1 and SLC7A11 gene expression, changes in the total number of circulating tumor cells (CTCs) and evaluate markers of DNA damage on CTCs, and tumor NAE1 and UBC12 protein expression.
Clinical Trials in Progress: Section not applicable.Conclusion
This study has been approved by the Cancer Therapy Evaluation Program (CTEP)/NCI and will open through the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) in August 2019.