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Sacha I Rothschild



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    MA 15 - Lung Cancer Biology II (ID 670)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 15.11 - CCNE1, PTGS2, TGFA and WISP2 Predict Benefit from Bevacizumab and Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer (SAKK19/09) (ID 9592)

      16:55 - 17:00  |  Presenting Author(s): Sacha I Rothschild

      • Abstract
      • Presentation
      • Slides

      Background:
      Bevacizumab (Bev; Avastin[®]) is a monoclonal antibody against the vascular endothelial growth factor. No predictive biomarkers for the use of Bev have been established so far. We aimed identifying genes predictive for progression-free survival (PFS) and overall survival (OS) of patients treated in the trial SAKK19/09 (NCT01116219).

      Method:
      SAKK19/09 was a non-randomized phase II trial with two sequential cohorts including patients with non-squamous NSCLC and EGFR wild-type. In Cohort 1, 77 patients were treated with cisplatin (C) 75mg/m[2], pemetrexed (Pem) 500mg/m[2] and Bev 7.5mg/kg, followed by Bev+Pem maintenance. Cohort 2 included 52 patients treated with C+Pem followed by Pem maintenance. RNA was isolated from baseline tumor tissue sections and processed for gene expression analysis by Nanostring. Using the Nanostring nCounter® System (Nanostring Technologies) gene expression of 201 genes, including 6 housekeeping genes was measured using a custom-designed codeset. For each gene, a Cox regression was performed with normalized gene expressions, treatment and the interaction for PFS and OS. No adjustment for multiple testing was done.

      Result:

      Gene Accession HR (95% confidence interval) p-value of interaction
      Cohort 1 Cohort 2
      Potential predictive markers for PFS
      AURKB NM_004217 1.09 (0.84-1.42) 0.78 (0.61-0.99) 0.0481
      CCNE1 NM_001238 1.09 (0.87-1.36) 0.73 (0.53-1.02) 0.0312
      CDKN2B NM_004936.3 0.80 (0.67-0.95) 1.10 (0.85-1.43) 0.0375
      MMP2 NM_004530.2 0.81 (0.67-0.97) 1.10 (0.91-1.34) 0.0258
      PTGS2 (COX-2) NM_000963.1 1.29 (1.06-1.58) 0.90 (0.78-1.04) 0.00352
      TGFA NM_003236.2 1.13 (0.94-1.37) 0.74 (0.53-1.03) 0.0452
      WISP2 NM_003881.2 0.82 (0.69-0.98) 1.24 (1.02-1.51) 0.0015
      Potential predictive markers for OS
      CCNE1 NM_001238 1.08 (0.86-1.36) 0.71 (0.49-1.02) 0.0324
      PTGS2 (COX-2) NM_000963.1 1.35 (1.10-1.65) 0.81 (0.69-0.95) <0.0001
      TGFA NM_003236.2 1.17 (0.96-1.43) 0.55 (0.33-0.91) 0.00352
      WISP2 NM_003881.2 0.87 (0.73-1.03) 1.14 (0.92-1.42) 0.0314
      We analyzed 99 patient samples (61 in Cohort 1; 38 in Cohort 2) with 201 genes at baseline. We found 7 genes potentially predictive for PFS (AURKB, CCNE1, CDKN2B, MMP2, PTGS2, TGFA, WISP2), 4 of which were also potentially predictive for OS (CCNE1, PTGS2, TGFA and WISP2) (Table 1).

      Conclusion:
      We identified several potentially predictive genes for Bev activity in combination with chemotherapy. Several of these (AURKB, CCNE1, CDKN2B, TGFA) have previously been shown to play an important role in cell cycle regulation and cell proliferation supporting the hypothesis that Bev supports chemotherapy activity. Notably, also a gene involved in inflammation (PTGS2) was significantly predictive for outcome. Further work is ongoing to explore changes in gene expression using tumor rebiopsies at progression.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-056 - SAKK 16/14 – Perioperative Anti-PD-L1 Antibody Durvalumab in Patients with Stage IIIA(N2) Non-Small Cell Lung Cancer (NSCLC) (ID 7902)

      09:30 - 09:30  |  Presenting Author(s): Sacha I Rothschild

      • Abstract

      Background:
      Improving the outcome of locally advanced non-small cell lung cancer (NSCLC) is one of the major challenges in thoracic oncology. SAKK substantially contributed to establish a standard of care for patients with stage III NSCLC: The trial SAKK 16/96 established neoadjuvant chemotherapy with three cycles of cisplatin and docetaxel. The randomized trial SAKK 16/00 showed no benefit by adding radiotherapy as third treatment modality to chemotherapy and surgery. Our results consistently showed a 5-year overall survival (OS) of 37%. However, it seems very difficult to further improve the OS by conventional therapies.

      Method:
      This is a single-arm phase II clinical trial designed to evaluate the addition of perioperative immunotherapy with the anti-PD-L1 antibody durvalumab to the previously established standard of care for stage IIIA(N2) patients, which is based on the trials SAKK 16/96 and SAKK 16/00. Eligible patients with WHO performance status 0-1 and age of 18-75 years must have pathologically proven NSCLC stage IIIA(N2) (T1-3 N2 M0) according to the 7th edition of the TNM classification, irrespective of histological subtype, genomic aberrations or PD-L1 expression status. Tumor tissue has to be available for the mandatory translational research. Patients whose tumor is deemed resectable at diagnosis receive three cycles of chemotherapy with cisplatin 100 mg/m[2 ]and docetaxel 85 mg/m[2] every three weeks followed by two cycles of durvalumab 750 mg every two weeks. Following surgery, patients will be treated with durvalumab 750 mg every two weeks for 12 months. Patients with R1/R2 resection and patients with extracapsular spread of mediastinal lymph node metastases may undergo standard radiotherapy prior to adjuvant treatment with durvalumab. The primary endpoint of the trial is event-free survival at 12 months. Secondary endpoints include OS, objective response, nodal down-staging, complete resection, pattern of recurrence and toxicity. Additionally, a large translation research program accompanies the trial investigating potential predictive biomarkers of anti-PD-L1 therapy.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable