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Eric Santoni Rugiu



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    P3.08 - Oligometastatic NSCLC (Not CME Accredited Session) (ID 974)

    • 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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      P3.08-18 - Changing Resistance Mechanisms in Rebiopsies of ALK-Positive NSCLC During Multiple Lines of Therapy: ALK/BRAF-Mutations Followed By EMT (ID 11203)

      12:00 - 13:30  |  Author(s): Eric Santoni Rugiu

      • Abstract
      • Slides

      Background

      4-7% of NSCLC patients harbor the oncogenic ALK-rearrangements and may obtain clinical benefit from different ALK-inhibitors. Despite long remissions, resistance inevitably appears in alternative dominating forms. We present a case of a 38-year old male with metastatic ALK-positive NSCLC. The patient received four consecutive ALK-TKIs and two lines of chemotherapy in-between. Significant clinical benefit was observed during different ALK-TKIs, as well as resistant ALK- and BRAF-mutations, and rapid progression shortly before death associated with phenotypical changes related to epithelial-mesenchymal transition (EMT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The diagnostic biopsy from cervical lymph nodes showed ALK-positive adenocarcinoma-metastasis with fusion variant 2 of EML4-ALK rearrangement. To identify TKI-resistance mechanisms during treatment, 4 rebiopsies from new metastatic lesions were analyzed histologically and by IHC, FISH and NGS. Additionally, two liquid biopsies were performed.

      4c3880bb027f159e801041b1021e88e8 Result

      The treatment was initiated by Crizotinib. After 10 months, the 1st rebiopsy from new hepatic metastases showed a new p.C1156Y-mutation.The patient then received Cisplatin/Vinorelbine, progressed after two cycles and received 3rd line Ceritinib. The 2nd rebiopsy from new metastasis appearing 8 months later displayed persistence of ALK-fusion and p.C1156Y, but also new p.D1203N ALK- and p.V600E BRAF–mutations. Therapy was changed to 4th line Alectinib. A 3rd rebiopsy taken 4 months later from progressing sites revealed persisting ALK-fusion without p.C1156Y and p.D1203N mutations, and still p.V600E BRAF-mutation. No mutations were detected in plasma cfDNA 3 months later. Due to mixed response Pemetrexed was added and the patient had regression for a year. At subsequent progression a 4th rebiopsy from new lesions revealed maintained ALK-fusion without any ALK- or BRAF-mutations. Histology (appearance of spindle cells) and IHC (strong positivity for the mesenchymal marker Vimentin, loss of the epithelial marker E-cadherin) revealed phenotypical changes related to EMT. A liquid biopsy did not show any DNA-mutations either. Meanwhile, 6th line Lorlatinib was initiated without response. The patient died 34 months after initial diagnosis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Following the treatment course of this case we observed heterogeneous and transitional mechanisms of resistance to different ALK-TKIs, such as secondary ALK-mutations, BRAF-mutation, and phenotypical changes consistent with EMT. This resistance heterogeneity suggests a continuously changing state of the disease. Sequential use of different ALK-TKIs and combination therapies may allow long responses with satisfactory quality of life, however phenotypical EMT-related changes remain a significant hurdle for TKI-based therapy that may explain lack of response to 3rd generation’s ALK-TKI, despite preserved ALK-positive status of the tumor.

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