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J. Patel
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-016 - EML4-ALK Fusion in a NSCLC Patient Detected by High Sensitivity Circulating Tumor DNA Assay Empowers Targeted Therapy Decisions (ID 2259)
09:30 - 09:30 | Author(s): J. Patel
- Abstract
Background:
The National Comprehensive Cancer Network (NCCN) non-small cell lung cancer (NSCLC) guidelines recommend genomic testing of seven genes in order to determine appropriate targeted therapy, including fusions in the anaplastic lymphoma kinase (ALK) gene which may be highly responsive to matched therapies. Tissue-based approaches to determine the tumor’s genetic status are often hampered by patient intolerance to repeat biopsy or insufficient tissue. Novel digital sequencing technology of plasma cell free circulating tumor DNA (ctDNA) allows assessment of these biomarkers without an invasive tissue biopsy.
Methods:
A 58 year-old woman was diagnosed with metastatic lung adenocarcinoma with bone predominant metastatic disease in February 2013. Despite histologic confirmation of adenocarcinoma, tissue was insufficient for genotyping despite multiple attempts at biopsy. She was treated empirically with carboplatin/pemetrexed with initial response, suffered from symptomatic progression in bone and underwent cell free circulating tumor DNA testing. Assessment of ctDNA levels using a comprehensive 68-gene digital sequencing[TM ]panel (Guardant360) with high sensitivity (detection of single nucleotid variants, focal gene amplifications in 16 genes, EGFR indels and fusions in ALK, ROS1, RET and NTRK1) in 87%+ of advanced cancer patients) and ultra-high specificity (>99.9999%) was performed on a blood sample from the patient.
Results:
Analysis of the patient’s ctDNA revealed an EML4-ALK fusion at 0.06% mutant allele fraction, which is equivalent to a single mutant molecule in a 10 mL tube of blood. This result was repeated in a second tube of blood, and two DNA fragments with the EML4-ALK fusion breakpoint were found. The patient also had a single nucleotide variant (R386G) in the AR gene at 0.25% and JAK2 V617F variant at 0.93% concentration. Crizotinib therapy was initiated on the basis of the EML4-ALK fusion and clinical improvement has already been noted. Repeat ctDNA measurements are planned and will be correlated with clinical response parameters based on RECIST criteria and protein-based tumor marker levels. This information will be reported at the time of presentation.
Conclusion:
To our knowledge, this is the first case report of EML4-ALK fusion identified in the clinical setting via biopsy-free circulating tumor DNA analysis. With single molecule sensitivity, this simple blood test was able to identify a therapeutic option in a patient who was unable to undergo tissue-based NGS.
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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): J. Patel
- 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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