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Jun Zhang



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    OA12 - Novel Therapies in MET, RET and BRAF (ID 921)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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      OA12.06 - Mutational Landscape of BRAF V600E Positive Lung Cancer Patients Following BRAF Directed Therapy Failure (ID 13540)

      16:10 - 16:20  |  Author(s): Jun Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      BRAF V600E mutation is identified as molecular drivers in 1-2% of lung adenocarcinomas and predicts response to combination BRAF and MEK inhibitors. Little is known about molecular mechanisms of acquired resistance to these therapies for lung cancer patients with BRAF V600E mutations, partially due to a lack of representative cancer models.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified patients with BRAF V600E mutated lung cancer who were progressing after initial response to a BRAF/MEK inhibitor combination in 5 academic institutions in the US. Potential molecular mechanisms of resistance were explored by comparing pre- and post-therapy results from comprehensive tissue and/or the Guardant360 and FoundationACT plasma-based next generation sequencing assays.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 6 patients. Prior to treatment with a BRAF/MEK inhibitor combination, four patients had received at least one line of chemotherapy and immune checkpoint inhibitor monotherapy, one had received chemotherapy only and one was treatment naïve. Five patients received dabrafenib/trametinib and one vemurafenib/cobimetinib combination. All 6 patients achieved a partial response. Progression free survival (PFS) ranged from 3 to 15 months (median 9.5 months). At the time of progression, all patients had the BRAF V600E mutation re-identified in their samples. Additionally, there was one patient with a new AKT1 E17K and a new KRAS G12A mutation, one patient with a new VHL R167Q mutation and one patient with a new TP53 splice site indel mutation at the time of progression. Another two patients had AKT1 E17K mutations that were present prior to BRAF/MEK inhibitor therapy. They both had oligoprogression, one in lymph nodes and one in the brain after 5.2 and 3 months, respectively; both continued on dabrafenib and trametinib combination therapy after radiation treatment to the progressing sites. Interestingly, co-occurrence of AKT1 E17K and BRAF V600E mutations is rare in the TCGA data, but was identified in three of six patients in our case series. Finally, we have established a BRAF V600E positive lung adenocarcinoma cell line from a TKI naïve patient for further functional studies of drug resistance.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Comprehensive molecular testing can identify potential resistance mechanisms following progression of BRAF V600E positive lung cancer to TKI therapy. AKT1 mutations were common as co-alterations in BRAF V600E mutated lung adenocarcinoma before and after targeted therapy and may contribute to drug resistance. The development of patient-derived cell line models may assist in the identification and validation of drug resistance mechanisms, and may help devise strategies to overcome drug resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 961)

    • 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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      P2.12-02 - Phase II Study of Combination of Nab-Paclitaxel and Gemcitabine for Relapsed Small Cell Lung Cancer (SCLC) (ID 13912)

      16:45 - 18:00  |  Author(s): Jun Zhang

      • Abstract

      Background

      Background: Almost all patients with extensive stage and two-thirds of limited stage small cell lung cancer develop disease recurrence or relapse after initial therapy. Most of these patients receive Topotecan as their subsequent therapy, which across multiple studies have shown response rates of approximately 15%. Though some of the newer agents have shown promising efficacy in biomarker selected patient-population;populations, ,in non-selected patients with relapsed SCLC, however, response rates with Nivolumab, Nivolumab in combination with Ipilimumab and Rovalpituzumab were only 10%, 23% and 18%, respectively. Among the conventional chemotherapies, both Gemcitabine and Paclitaxel have shown single agent activity in relapsed-refractory SCLC. Therefore, we hypothesized that combination of Gemcitabine and Nab-Paclitaxel will have additive effect, which will lead to improvement in therapeutic response compared to current standard of care. Based on the toxicity profile of this regimen in patients with advanced pancreatic cancer, we believe it will be better tolerated than Topotecan.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: This is a single-arm phase II study. Primary end-point of the study is response rate as defined per RECIST 1.1 criteria. Eligible subjects will receive gemcitabine 1000 mg/m2 and nab-paclitaxel 100 mg/m2 on days 1 & 8 of every 21-day cycle. Response assessment will occur every 6 weeks. Target accrual is 32 with 28 evaluable subjects. This would achieve 82% power to detect a difference of 20% to current standard of care therapy, using a one-sided binomial exact test. The results assume that the current standard of care (Topotecan) has a response rate of 15%. Secondary end-points include overall survival, time to progression and treatment-related toxicity

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53