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Jianhua Chang



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    JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)

    • Event: WCLC 2018
    • Type: Joint IASLC/CSCO/CAALC Session
    • Track: Screening and Early Detection
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
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      JCSE01.11 - Dynamic ctDNA Monitoring Revealed Novel Resistance Mechanisms and Response Predictors of Osimertinib Treatment in East Asian NSCLC Patients (Now Available) (ID 14716)

      10:35 - 10:45  |  Presenting Author(s): Jianhua Chang

      • Abstract
      • Presentation
      • Slides

      Background

      Advanced NSCLC patients, harboring EGFR T790M, exhibit marked diversity in tumor behavior and response to AZD9291, yet a discriminable molecular profile remains elusive. In addition, although EGFRC797S was involved in 30% of AZD9291 resistance cases in Western patients, mechanisms for the rest patients remain unclear, especially for the East Asian population. We utilized circulating tumor DNA (ctDNA) profiling to conduct dynamic monitoring in patients undergoing AZD9291, thus characterizing mutational heterogeneity and genomic evolution.

      Longitudinal plasma samples were collected before, during and post of the AZD9291 treatment in Chinese NSCLC patients with acquired T790M mutation. A ctDNA panel, spanning 160KB of human genome, was used to perform capture-based targeted sequencing that comprises critical exons and introns of 168 genes. The EGFR mutation abundance and dynamic changes of allele fraction (AF) were analyzed with progression-free survival (PFS) after AZD9291 treatment.

      A total of 61 samples were collected longitudinally from 14 patients, of which 9 have experienced progressive disease (PD). Six patients exhibited a rebound of ctDNA prior to radiographic PD, suggesting the potential of ctDNA in early detection of PD. Several acquired mutations were detected with the AZD9291 resistance, including newly identified EGFR G796S, L792H/F/R/V, V802F, V843I mutations, expect for the previously reported RB1 and EGFR C797S, L718Q mutations. Patients with a higher ratio of T790M and EGFRactivating mutation at baseline had a significantly longer PFS (9.6m vs 4.5m, p=0.008). A lower ratio of EGFRactivating mutation AF compared to baseline at first follow-up was significantly correlated with a longer PFS (8.5m vs 5.0m, p=0.027). Furthermore, patients harboring other known driver mutations in addition to T790M at baseline had an inferior PFS (4.9m vs 7.8m, P=0.039).

      Several novel resistance mechanisms were identified by ctDNA monitoring in the East Asian patients treated with AZD9291. Relative AF of T790M, changes of AF after treatment and the presence of concurrent driver mutations at baseline could predict clinical benefit of AZD9291 treatment.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-95 - Crizotinib Treatment in 29 Advanced NSCLC Chinese Patients with ROS1 Rearrangement——A Single Chinese Cancer Institute Experience (Now Available) (ID 13958)

      16:45 - 18:00  |  Author(s): Jianhua Chang

      • Abstract
      • Slides

      Background

      Approximately 1%~2% of NSCLC patients harbor ROS1 rearrangement. Crizotinib, a tyrosine kinase inhibitor that targets ALK, MET and ROS1, has shown marked antitumor activity in patients with ROS1-positive advanced NSCLC.

      Method

      A total of 29 patients with ROS1 rearrangement advanced or metastatic NSCLC were treated with crizotinib between Apr 1st, 2016 and Feb 6th, 2018 at Shanghai Cancer Center, Fudan University. Patients were administered with oral crizotinib at dose of 250 mg twice daily.

      Result

      The median age was 51 years old. Twenty patients (69.0%) were female. Twenty-three(79.3%) were never-smokers. Six patients (20.7%) had brain metastases. Sixteen patients (55.2%) had received chemotherapy prior to crizotinib therapy. Patients’ characteristics were showed in table 1. The ORR and DCR were 65.5% and 93.1%, respectively. The estimated median PFS has not been reached yet. Transaminases increase (15/29,51.7%), vision disorder (6/29,20.7%), blood creatinine increase (6/29,20.7%), vomiting (6/29,20.7%), fatigue (5/29,17.2%) and diarrhea (5/29,17.2%)
 were the most commonly reported adverse effects. Two patients (6.9%) discontinued crizotinib because of crizotinib-related vomiting, one of whom had reduced to 200mg twice daily.

      table 1 .jpg

      Conclusion

      Crizotinib was effective and well tolerated in Chinese patients with ROS1-positive, advanced NSCLC in real-world clinical practice.

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      P1.01-98 - A Phase IIIb Trial of Afatinib in EGFRm+ NSCLC: Analyses of Outcomes in Patients with Brain Metastases or Dose Reductions (ID 12906)

      16:45 - 18:00  |  Author(s): Jianhua Chang

      • Abstract

      Background

      We previously reported interim results of a large (n=479) open-label, single-arm Phase IIIb study of afatinib in EGFR TKI-naïve patients with EGFRm+ NSCLC, in a setting similar to ‘real-world’ practice (Wu et al, WCLC, 2017). In this broad population of Asian patients, the tolerability profile of afatinib was predictable and manageable. Adverse events (AEs) were consistent with the LUX-Lung 3, 6 and 7 trials; 3.8% of patients discontinued due to drug-related AEs. Progression-free survival (PFS) and time to symptomatic progression (TTSP) was encouraging, in patients with both common and uncommon EGFR mutations. TTSP data suggested effective treatment beyond progression. Here, we assess the impact of baseline brain metastases and use of dose reductions on efficacy outcomes.

      Method

      Patients with locally advanced/metastatic EGFRm+ NSCLC were recruited in China, Hong Kong, India, Singapore and Taiwan. Afatinib 40mg/day was given until disease progression (investigator-assessed) or lack of tolerability. Treatment-related AEs could be managed by protocol-specified tolerability-guided dose adjustment.

      Result

      At data cut-off (13 Feb 2017), patient characteristics were as follows: median age, 59.0 years; female, 52.4%; EGFR mutations: Del19+/-L858R+/-uncommon, 86.0%; uncommon only, 14.0%; ECOG PS0, 19.8%; PS1, 78.1%. Prior chemotherapy lines: 0, 59.7%; 1, 30.1%; ≥2, 10.2%.

      Overall, dose reductions from 40mg/day to 30mg/day occurred in 119 patients (25%). Incidences of the most frequently reported AEs before and after dose reduction were (any grade): diarrhea, 96/51%; rash/acne, 69/58%; stomatitis, 65/42%; (≥grade 3) diarrhea, 27/4%; rash/acne, 24/11%; stomatitis, 11/5%. A total of 96 patients had a dose reduction during the first six months; median PFS in this subgroup was 14.1 months (95% CI: 10.0–19.3) versus 11.33 (10.7–13.6) months in those who remained on the starting dose (n=383); HR=1.37 (1.01–1.85), p=0.041. Median TTSP was 17.7 (13.5–23.7) and 14.7 (12.7–17.0) months, respectively; HR=1.26 (0.92–1.72), p=0.15.

      Among 92 patients (19.2%) with brain metastases at baseline, median PFS was 10.9 (8.3–14.3) months, versus 12.4 (10.8–13.9) months in those without metastases (n=387); HR=1.23 (0.91–1.65), p=0.18. Median TTSP was 14.8 (12.7–20.7) and 15.4 (12.9–18.0) months, respectively; HR=1.0 (0.71–1.40), p=1.0.

      Conclusion

      These findings demonstrate that tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related AEs, while maintaining therapeutic efficacy. TTSP was similar between patients with and without brain metastasis. This is additional evidence for the efficacy of afatinib in patients with brain metastases.

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-16 - Dynamic ctDNA Monitoring Revealed Novel Resistance Mechanisms and Response Predictors of Osimertinib Treatment in East Asian NSCLC Patients (Now Available) (ID 13861)

      16:45 - 18:00  |  Presenting Author(s): Jianhua Chang

      • Abstract
      • Slides

      Background

      Advanced NSCLC patients, harboring EGFR T790M, exhibit marked diversity in tumor behavior and response to AZD9291, yet a discriminable molecular profile remains elusive. In addition, although EGFRC797S was involved in 30% of AZD9291 resistance cases in Western patients, mechanisms for the rest patients remain unclear, especially for the East Asian population. We utilized circulating tumor DNA (ctDNA) profiling to conduct dynamic monitoring in patients undergoing AZD9291, thus characterizing mutational heterogeneity and genomic evolution.

      Method

      Longitudinal plasma samples were collected before, during and post of the AZD9291 treatment in Chinese NSCLC patients with acquired T790M mutation. A ctDNA panel, spanning 160KB of human genome, was used to perform capture-based targeted sequencing that comprises critical exons and introns of 168 genes. The EGFR mutation abundance and dynamic changes of allele fraction (AF) were analyzed with progression-free survival (PFS) after AZD9291 treatment.

      Result

      A total of 61 samples were collected longitudinally from 14 patients, of which 9 have experienced progressive disease (PD). Six patients exhibited a rebound of ctDNA prior to radiographic PD, suggesting the potential of ctDNA in early detection of PD. Several acquired mutations were detected with the AZD9291 resistance, including newly identified EGFR G796S, L792H/F/R/V, V802F, V843I mutations, expect for the previously reported RB1 and EGFR C797S, L718Q mutations. Patients with a higher ratio of T790M and EGFRactivating mutation at baseline had a significantly longer PFS (9.6m vs 4.5m, p=0.008). A lower ratio of EGFRactivating mutation AF compared to baseline at first follow-up was significantly correlated with a longer PFS (8.5m vs 5.0m, p=0.027). Furthermore, patients harboring other known driver mutations in addition to T790M at baseline had an inferior PFS (4.9m vs 7.8m, P=0.039).

      Conclusion

      Several novel resistance mechanisms were identified by ctDNA monitoring in the East Asian patients treated with AZD9291. Relative AF of T790M, changes of AF after treatment and the presence of concurrent driver mutations at baseline could predict clinical benefit of AZD9291 treatment.

      Only Active 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 or select "Add to Cart" and proceed to checkout.