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Zhi-Hong Chen
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MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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MA15.01 - Strong PD-L1 Expression Predicts Poor Response and de Novo Resistance to EGFR TKIs Among Non-Small Cell Lung Cancer Patients with EGFR Mutation (ID 12920)
13:30 - 13:35 | Author(s): Zhi-Hong Chen
- Abstract
- Presentation
Background
This study evaluated whether tumor expression of programmed death-ligand 1 (PD-L1) predicted the response of EGFR-mutated non-small cell lung cancer (NSCLC) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC between April 2016 and September 2017 at the Guangdong Lung Cancer Institute. None of them were enrolled in clinical studies, and their EGFR and PD-L1 statuses were simultaneously evaluated.
4c3880bb027f159e801041b1021e88e8 Result
Among the 101 eligible patients, strong PD-L1 expression significantly decreased the objective response rate (ORR) compared with those with weak or negative PD-L1 expression (35.7% vs 63.2% vs 67.3%, P=0.002) as well as shortened progression-free survival (PFS, 3.8months vs 6.0months vs 9.5months, P<0.001), regardless of EGFR mutation types (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% vs 30.2%, P=0.009). Notably, patients with de novo resistance had a high proportion of dual positive for PD-L1 and CD8 (46.7%, 7/15). Finally, one patient with de novo resistance to EGFR-TKIs and dual positivity for PD-L1 and CD8 experienced a favorable response to anti-PD-1 therapy.
8eea62084ca7e541d918e823422bd82e Conclusion
This study uncovered the adverse impact of PD-L1 expression on the efficacy of EGFR- TKIs, especially in those with de novo resistance NSCLC, which inclined to reshape an inflamed immune phenotype of dual positive for PD-L1 and CD8 and showed potential therapeutic sensitivity to PD-1 blockade.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MA15.06 - Circulating Tumor DNA Portrays the Resistance Landscape to a Novel Third Generation EGFR Inhibitor, AC0010 (ID 13641)
14:05 - 14:10 | Author(s): Zhi-Hong Chen
- Abstract
- Presentation
Background
In a Phase I/II dose-escalation and expansion study conducted at Guangdong Lung Cancer Institute, AC0010 demonstrated promising efficacy and good tolerability in advanced NSCLC patients with EGFR T790M-mediated resistance to previous EGFR TKIs, (NCT02330367). As disease progression (PD) with EGFR T790M-directed therapy also emerges over time, we investigated the resistance mechanisms to AC0010 in this study.
a9ded1e5ce5d75814730bb4caaf49419 Method
Serial ctDNA samples obtained from patients who developed PD with AC0010 were analyzed using ultra-deep sequencing capturing 295 cancer-related genes. Alterations that were absent before treatment and acquired at PD or that increased in abundance during treatment were identified as putative resistance mechanisms.
4c3880bb027f159e801041b1021e88e8 Result
Longitudinal plasma samples were obtained from 23 patients who progressed on AC0010 (data cut-off October 14, 2016; figure1). Putative resistance mechanisms to AC0010 were identified in 19/23 patients (>1 putative resistance mechanism was detected in some patients). EGFR amplification was the predominant resistance mechanism (21.1% [4/19 patients]), followed by TP53 loss of heterozygosity (15.8% [3/19]). EGFR C797S mutation, Met amplification and mutations in the PI3KCA pathway each occurred in 10.5% of patients (2/19). SCLC transformation, ERBB2 amplification, CD79A_A32G mutation, CDKN2A_R80 mutation, CRLF2 amplification, MLH1 amplification, Rb1 loss, and concurrent rise in the allelic fraction of tumor suppressor gene TP53 and Rb1 were each detected in 5.3% of patients (1/19). In a patient with PD following single-agent AC0010 and EGFR amplification as the putative resistance mechanism to AC0010, subsequent treatment with AC0010 plus nimotuzumab (EGFR monoclonal antibody) successfully overcame resistance, resulting in a response that lasted for 7.7 months.
8eea62084ca7e541d918e823422bd82e Conclusion
The resistance landscape to AC0010 appears to differ from that described previously with osimertinib. In this cohort of patients in China, EGFR amplification was the predominant resistance mechanism to AC0010 and could be potentially overcome by EGFR dual inhibition.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.03 - Biology (Not CME Accredited Session) (ID 935)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.03-34 - Combined Molecular and Radiological Evaluation Unveils Three Subtypes of Disease Progression to a Third Generation EGFR TKI (ID 12055)
16:45 - 18:00 | Author(s): Zhi-Hong Chen
- Abstract
Background
The definition of disease progression (PD) to EGFR TKIs has evolved from RECIST to a combination of clinical and RECIST evaluation. Patients with dramatic, local or gradual progression to third generation EGFR TKIs have been tailored to different subsequent treatment strategies. However, little is known about progression to third generation EGFR TKIs from molecular perspective.
a9ded1e5ce5d75814730bb4caaf49419 Method
Longitudinal plasma samples were collected from T790M-positive patients who progressed on a third generation EGFR TKI AC0010 in a phase I/II study in Guangdong Lung Cancer Institute. A pre-defined and unified molecular and radiological evaluation of PD were performed. Ultra-deep sequencing capturing 295 cancer-related genes was performed to track the changes in ctDNA to depict molecular PD, which was defined by acquired SNV/SCNV, or ≥20% increase in allelic fraction/copy number of pre-existing SNV /SCNV or both. Radiological PD was defined by RECIST.
4c3880bb027f159e801041b1021e88e8 Result
As of October 2016, 102 serial plasma samples from 23 patients with clinical PD were included. Three subtypes of PD to AC0010 were revealed (Fig1). Molecular PD occurred prior to radiological PD in 43.5% of patients (10/23), with an average lead time of 3.0 months. Molecular PD occurred concurrently with radiological PD in 39.1% of patients (9/23). Interestingly, 17.4% of patients (4/23) experienced radiological PD prior to molecular PD, with molecular PD occurred during AC0010 continuation beyond progression (CBPD) in 3 patients. Of patients experienced clinical stable PD in extracranial lesions, radiological PD occurring prior to molecular PD group (n=2) demonstrated longer duration of AC0010 CBPD than molecular PD occurring prior to (n=3) or concurrently with radiological PD groups (n=4) (Median, 5.6 months vs. 1.9 months vs. 1.8 months).
8eea62084ca7e541d918e823422bd82e Conclusion
Our study revealed 3 distinct subtypes of PD to AC0010, providing insights into PD by combining molecular and radiological evaluation and might guide the optimal time for treatment switch and personalized subsequent treatments.
6f8b794f3246b0c1e1780bb4d4d5dc53
