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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
P1.01-035 - A Next Generation Sequencing and Characteristics Based Model for Predict Clinical Benefit of Advanced NSCLC Patients (ID 9208)
09:30 - 16:00 | Author(s): L. Zhang
The development of targeted therapies has revolutionized the treatment of non-small cell lung cancer. Interrogating the status of driver mutations has become routine practice. In this study, we applied next-generation sequencing to investigate the association between molecular signature and clinical benefit.
We performed capture-based targeted ultra-deep sequencing on 204 samples obtained from NSCLC patients at a single center, including 93 FFPE, 70 fresh tissue and 41 plasma samples. One hundred and twenty two samples were subjected to a panel consisting of 8 driver genes; 50 samples were subjected to a 56-gene panel. The remaining 32 samples were subject to a 168 gene panel.
In 159 TKI-naïve patients, driver mutation was identified in 95.2% of (79/83) patients using the 8-gene panel; among them, 65.1% (54/83) carried EGFR mutations. Larger panels identified mutations in 68.1% of patients; 21% carried mutations other than driver mutations. Treatment-naïve patients were primarily subject to the 8-gene panel; in contrast, patients progressed on chemotherapy were subject to larger panels. Seventy-two percent of patients (80/111) undergone matched targeted therapy (MTT) according to sequencing results had a significantly longer PFS than 29 patients who chose chemotherapies despite the fact of harboring driver (p=4.58x10[-4] HR=0.342, 95% CI: 0.158, 0.74). Next, we investigated whether the number of EGFR mutations a patient carries and the presence of concurrence EGFR amplification have an effect on PFS. Our data revealed that both parameters are not associated with PFS. Among 46 patients receiving chemotherapy, patients with KRAS mutations were associated with a shorter PFS, 133 days vs 207 days (p= 0.073, HR=2.06 95% CI; 0.791, 5.36). For TKI-naïve patients, primary tumor tissue was collected from 86 patients and tumor tissue from metastatic lymph nodes was collected from 35 patients. Interestingly, we observed that lymph node samples had a higher maximum mutation allelic fraction (MAF) than primary lung tumor samples in patients with distance metastasis, especially with visceral metastasis (p=0.0986); such trend was not observed in patients without distant metastasis. We also analyzed samples obtained after TKI-treatment. Among 36 TKI-treated patients, patients with visceral metastasis were more likely to harbor TP53 mutations (p=0.04), which were primarily missense mutations not loss of function mutations, primarily seen in tumorigenesis. TP53 missense mutations can potentially promote distant visceral metastasis after the development of resistance to TKIs.
Our study highlighted the utility of sequencing-based screening technologies and characteristics in providing treatment guidance.
P1.01-037 - Circulating Tumor DNA Clearance During Treatment Associates with Improved Progression-Free Survival (ID 9653)
09:30 - 16:00 | Author(s): L. Zhang
Therapeutic selection has been shown to lead to marked clonal evolution, thus revealing limitations in imaging scan as a monitoring method, which does not reflect biological processes at a molecular level. However, currently, response assessment of patients with non-small cell lung cancer (NSCLC) primarily relies on imaging scans, necessitating the development of methodologies for dynamic monitoring of treatment response. We evaluated ctDNA as a tumor clonal response biomarker.
We screened 831 advanced NSCLC patients with a mixture of prior treatment exposure by performing capture-based ultra-deep targeted sequencing on plasma samples using a panel consisting of 168 NSCLC-related genes. Eighty-six patients with driver mutations and a minimum of 2 evaluation points in addition to baseline were included for further analysis.
At baseline, 79.9% patients harbored at least one mutation from this panel; the remaining 20.1% had no mutation detected. Sixty-nine percent of patients (570/831) harbored driver mutation. Patients harboring 2 mutations or fewer at baseline had a median progression-free survival (PFS) of 7.4 months; in contrast, patients harboring more than 2 mutations had a median PFS of 3.8 months (P=6.6x10[-5 ]HR=0.34), suggesting a significant inverse correlation between number of mutations at baseline and PFS. Next, we evaluated the ability of ctDNA as a tumor clonal response biomarker in 86 patients with a minimum of 2 follow-ups. After a median follow-up of 314 days, 64 patients (74.4%) reached disease progression. During treatment, 46 patients, treated with either matched targeted therapy (MTT) or chemotherapy, had a minimum of one time of ctDNA clearance, occurring from 1.6 months to 7.5 months after the commencement of treatment, with a median PFS of 8.07 months, an overall response rate (ORR) of 41% and a disease control rate (DCR) of 93%. Median overall survival (OS) for this group has not reached. In contrast, 40 patients who had consistent detectable ctDNA throughout the course of treatment had a median PFS of 3.47months, a median OS of 425 days, an ORR of 20% and a DCR of 53%. Our data revealed that patients with a minimum of one time ctDNA clearance are associated with a better ORR (p=0.05), DCR (p=5.9x10[-5]), a longer PFS (p=5.4x10[-10 ]HR=0.21) and OS (p=2.3x10[-5 ]HR=0.21), regardless the type of treatment commenced and the time of evaluation.
This real world study comprising a heterogeneous population reveals the predictive and prognostic value of ctDNA and warrants further investigations to explore its clearance as a surrogate endpoint of efficacy.