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Mengzhao Wang
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OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships (ID 910)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 106
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OA10.07 - Resistance Mechanisms of Osimertinib in Chinese Non-Small Cell Lung Cancer Patients: Analysis from AURA17 Trial (ID 12693)
11:35 - 11:45 | Author(s): Mengzhao Wang
- Abstract
- Presentation
Background
Osimertinib is approved for metastatic NSCLC patients with EGFR T790M mutation after progression from TKI therapy. Despite impressive tumor responses, drug resistance usually develops. The resistance mechanisms of osimertinib are emerging but studies with large cohorts of Chinese patients and association with clinical outcomes are lacking. Here we report a biomarker study of osimertinib using plasma samples from 107 Chinese patients who had progressed by 24 months after LSFD (Oct. 2017) of AURA17 (NCT02442349), the 2nd-line pivotal trial in China.
a9ded1e5ce5d75814730bb4caaf49419 Method
Serial plasma cell-free DNA (cfDNA) were collected from baseline until progressive disease (PD) by investigator assessment. Capture-based 75-gene NGS panel with unique molecular index (UMI) system was used to identify resistance mechanisms to osimertinib by comparing paired cfDNA at baseline and PD. Droplet digital PCR (ddPCR) was used to dynamically monitor EGFR mutation changes (L858R, Ex19Del, T790M and C797S) during treatment course. Association of cfDNA biomarkers based on valid test results with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) from DCO3 (Mar. 20, 2018) was analyzed.
4c3880bb027f159e801041b1021e88e8 Result
The 107 patients were with ORR of 68.2%, median PFS of 8.2 months, and median OS of 21.5 months. Eight-two had detectable EGFR sensitizing mutations (L858R or Ex19Del) in their PD cfDNA samples. Among them, 15 had acquired EGFR C797S, all in cis with T790M, and with no enrichment for L858R or Ex19Del (6 and 9, respectively). The median time of C797S detection from plasma was 2.8 (1.2-8.4) months prior to PD. EGFR L718Q, I744T, C775Y, G796S/D, T854I mutations, or amplification were found in 11 patients. Aberrations in bypass tracks including AKT2, ALK, DDR2, ERBB2/3, HRAS, JAK1/2, KRAS, MET, NTRK1, PIK3CA, RIT1, etc. were observed in 45 patients.
Clearance of EGFR sensitizing mutations at weeks 3 of treatment was associated with favorable ORR (78.7% vs. 33.3%), PFS (9.6 vs. 4.0 months, p<0.001) and OS (21.5 vs. 11.7 months, p<0.001). Clearance of EGFR sensitizing mutations at weeks 6 of treatment was also associated with favorable ORR (80.0% vs. 36.8%) and PFS (8.3 vs. 4.2 months, p<0.001). Presence of T790M at PD was correlated with longer PFS (12.3 vs. 5.5 months, p<0.001) and OS (21.3 vs. 13.2 months, p=0.045). Acquired or enriched TP53 alterations at PD were associated with worse PFS (4.2 vs. 8.3 months, p=0.008).
8eea62084ca7e541d918e823422bd82e Conclusion
Our study revealed diverse resistance mechanisms to osimertinib in Chinese NSCLC patients and urged for new drug discovery or combination strategies to overcome this clinical challenge.
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-05 - Real-World Clinical Benefit of Continuing Crizotinib Beyond Progression Disease (CBPD) in Patients with Advanced ALK-Positive NSCLC. (ID 13353)
16:45 - 18:00 | Author(s): Mengzhao Wang
- Abstract
Background
Most ALK-positive NSCLC patients treated with crizotinib would ultimately develop progressive disease (PD), and continuing crizotinib beyond initial PD (CBPD) may be potentially beneficial. We aim to evaluate the survival outcomes of patients with crizotinib resistance in real-world setting and to explore the clinical efficacy of continuing CBPD treatment.
a9ded1e5ce5d75814730bb4caaf49419 Method
A total of 261 ALK-positive NSCLC patients treated with crizotinib experienced RECIST-defined PD and were included in this multi-center retrospective analysis. Clinicopathologic characteristics, progressive pattern, post-PD treatment and overall survival (OS) were compared between patients continuing CBPD and those not.
4c3880bb027f159e801041b1021e88e8 Result
140 patients who continued crizotinib after disease progression were allocated to CBPD group and others were non-CBPD group. Two-sided Chi-square test showed that patients who never smoked (P=0.047), with ECOG 0-1(P=0.001), isolated intracranial progression (P<0.001) and <median PFS of initial crizotinib (P=0.002) were more likely in the CBPD group. At the analysis, 84 patients had re-PD and the median duration of crizotinib treatment post-PD was 6.8 months (95%CI: 3.639-9.869). The median OS for the overall population from the time of PD (post-PD OS) was 15.3 months (95%CI: 11.376-19.181), and was significantly longer in CBPD patients than non-CBPDs (24.1 months vs. 8.5 months, 95% CI: 0.326-0.669, HR 0.467, P<0.001). Furthermore, next-generation ALK inhibitors (ALKis) following crizotinib failure was associated with improved post-PD OS (24.9 months vs. 10.7 months, 95% CI: 0.307-0.686, HR 0.459, P<0.001).
8eea62084ca7e541d918e823422bd82e Conclusion
Continuing CBPD treatment after crizotinib resistance favorably impact survival outcomes of advanced ALK-positive NSCLC patients in the real-world. Next-generation ALKis may provide survival improvement, but comparative studies between different subsequent treatment options after PD on crizotinib are still needed.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-103 - Efficacy of Crizotinib in Chinese Non-Small Cell Lung Cancer Patients with Brain Metastasis: A Multicenter Retrospective Study (ID 12578)
12:00 - 13:30 | Author(s): Mengzhao Wang
- Abstract
Background
Brain metastasis in advanced non-small cell lung cancer (NSCLC) patients is often considered as a terminal stage. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) for ALK-rearranged NSCLC patients. Herein we conducted a multi-center retrospective study to explore how crizotinib affects the control of brain metastasis and survival outcomes among advanced ALK-rearranged NSCLC patients with brain metastasis in Chinese population.
a9ded1e5ce5d75814730bb4caaf49419 Method
We reviewed medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at five cancer centers in China from January 2013 to November 2017. Patients developing brain metastasis either before or during the crizotinib treatment were enrolled. Survival outcomes were analyzed with Kaplan-Meier method and prognostic factors were analyzed with multivariate COX analysis.
4c3880bb027f159e801041b1021e88e8 Result
A total of 174 patients were enrolled into this study, of whom 95 patients had baseline brain metastasis and 79 patients developed brain metastasis during crizotinib treatment. Among patients with baseline brain metastasis, the median intracranial progression-free survival (PFS) was 15.34 months [95% confidence interval (CI): 10.62-20.07] and median overall survival (OS) was 53.38 months (95%CI: 30.58-76.17). The intracranial objective response rate (ORR) was 17.1%, and the intracranial disease control rate (DCR) was 88.6%. Multivariate COX analysis revealed that patients receiving first-line crizotinib [>first-line vs. first-line, hazard ratio (HR): 2.44, 95%CI: 1.05-5.68, p=0.038], withtout intracranial progression during crizotinib treatment (with vs. without intracranial progression, HR: 18.68, 95%CI: 2.43-143.31, p=0.005) were associated with better OS, while age, sex, number of brain lesions, and operation/radiation therapy for brain metastasis were not significantly associated with OS. Among patients developing brain metastasis during crizotinib treatment, the median OS was 35.64 months (95%CI: not reached). Multivariate COX analysis revealed that brain progression only (brain progression only vs. both brain and extracranial progression, HR: 0.23, 95%CI: 0.08-0.71, p=0.011) was associated with better OS, while age, sex, line of crizotinib treatment, treatment after progression and operation/radiation therapy for brain metastasis were not significantly associated with OS.
8eea62084ca7e541d918e823422bd82e Conclusion
Advanced ALK-rearranged NSCLC patients with baseline brain metastasis could still benefit from crizotinib treatment. However, brain progression during crizotinib treatment may be associated with worse survival outcomes.
6f8b794f3246b0c1e1780bb4d4d5dc53
