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S.E. Dahlberg
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.04 - A Randomized Phase 2 Trial of Cabozantinib, Erlotinib or the Combination as 2nd or 3rd Line Therapy in EGFR Wild-Type NSCLC: ECOG-ACRIN E1512 (ID 404)
18:45 - 18:50 | Author(s): S.E. Dahlberg
- Abstract
Background:
Cabozantinib (C) is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2 & RET. MET is involved in tumor differentiation & VEGFR2 is a mediator of angiogenesis. Erlotinib (E) is FDA approved for the treatment of NSCLC.
Methods:
The primary objective of this randomized phase 2 study was to compare progression-free survival (PFS) of pts treated with E vs. C, & E vs E+C; each comparison had 91% power to detect a PFS hazard ratio (HR) of 0.5 with a 1-sided 0.10-level test stratified on prior number of therapies & ECOG PS. Secondary objectives included overall survival (OS), RECIST 1.1 response & CTCAE v4 toxicity. Pts were selected with previously treated (1-2 regimens) metastatic non-squamous EGFR wt NSCLC. Submission of archival tissue for central MET IHC testing was required. Oral daily dosing was: E-150 mg; C-60 mg; E+C-150 mg E, 40 mg C. Imaging was performed every 8 weeks. Pts optionally crossed over to E+C following progression on E or C.
Results:
125 pts were enrolled, of which 115 were eligible & treated (E, n=39; C, n=39; E+C, n=37). Pt characteristics were balanced between arms except for lower rate of brain mets history on E (p=0.02). Median follow up is 8.5 m. Compared with E (median 1.9 m), PFS was significantly improved on C (3.9 m, HR 0.33, p=0.0002, 80% CI 0.22-0.49) & E+C (4.1 m, HR 0.31, p=0.0002, 80% CI 0.21-0.46). Similarly, compared with E (median 4.0 m), OS was significantly improved on C (HR 0.52, p=0.02) & E+C arm HR 0.50, p=0.02). Grade 3-4 treatment-related hypertension & mucositis were higher on C and grade 3-4 diarrhea was higher on E+C. Overall worst grade toxicities were also significantly higher on C and E+C. MET IHC results were available on 88 patients from the primary analysis & 85% were positive (1-3+ membrane or cytoplasm staining with MET4 antibody). There was no correlation between MET status and PFS.
Conclusion:
C & C+E significantly improved PFS over E alone in pts with EGFR wt NSCLC. Cabozantinib-based regimens are promising for further investigation in this patient population. Funded by ECOG-ACRIN and NCI Contract No. HHSN261200800001E.
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PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 1
- Moderators:T. Mok, F.R. Hirsch
- Coordinates: 9/09/2015, 10:45 - 12:15, Plenary Hall (Bellco Theatre)
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PLEN04.03 - Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505 (ID 1608)
11:07 - 11:19 | Author(s): S.E. Dahlberg
- Abstract
- Presentation
Background:
Adjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase 3 study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC. The primary endpoint was overall survival and secondary endpoints included disease-free survival and toxicity assessment.
Methods:
Patients with resected stage IB (>4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6-12 weeks of surgery and stratified by chemotherapy regimen, stage, histology and sex. All patients were to receive adjuvant chemotherapy consisting of a planned 4 cycles of every 3 week cisplatin at 75 mg/m[2] with either vinorelbine, docetaxel, gemcitabine or pemetrexed. Patients were randomized 1:1 to arm A (chemotherapy alone) or arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for 1 year. Post-operative radiation therapy was not allowed. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0.025-level test.
Results:
From July 2007 to September 2013, 1501 patients were enrolled. Patients were 49.8% male, predominantly white (87.9%) with a median age of 61 years. Patients enrolled had tumors that were 26.2% stage IB, 43.8% stage II and 30.0% stage IIIA and 28.2% of patients had squamous cell histology. Chemotherapy options were utilized with the following distribution: vinorelbine 25.0%, docetaxel 22.9%, gemcitabine 18.9% and pemetrexed 33.2%. At a planned interim analysis, with 412 of 676 overall survival events needed for full information (60.9%), though the pre-planned futility boundary was not crossed, the Data Safety Monitoring Committee recommended releasing the trial results based on the conditional power of the logrank test. At the time of interim analysis, with a median follow-up time of 41 months, the OS hazard ratio comparing the bevacizumab containing arm (Arm B) to chemotherapy alone (Arm A) was 0.99 (95% CI: 0.81-1.21, p=0.93). The DFS hazard ratio was 0.98 (95% CI: 0.84-1.14, p=0.75). Completion of treatment per protocol was 80% on Arm A and 36% on Arm B. Statistically significantly increased grade 3-5 toxicities of note (all attributions) included: overall worst grade (67% versus 84%); hypertension (8% versus 30%), and neutropenia (33% versus 38%) on Arms A and B, respectively. There was no significant difference in grade 5 adverse events per arm with 16 (2%) on arm A and 19 (3%) on arm B.
Conclusion:
The addition of bevacizumab to adjuvant chemotherapy failed to improve survival for patients with surgically resected early stage NSCLC.
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