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Jacques Cadranel



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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-25 - Targeting NRG1-Fusions in Lung Adenocarcinoma: Afatinib as a Novel Potential Treatment Strategy (ID 1805)

      09:45 - 18:00  |  Author(s): Jacques Cadranel

      • Abstract
      • Slides

      Background

      Neuregulin 1 (NRG1) gene fusions result in activation of ErbB2-/ErbB3-mediated signaling pathways, and may function as oncogenic drivers. NRG1 fusions have emerged as a potential therapeutic target across multiple tumor types, including non-small-cell lung cancer (NSCLC). Afatinib, a pan-ErbB-family blocker, may be a treatment option for patients with NRG1+ NSCLC, as supported by preclinical evidence and seven published case reports (Table).

      Method

      Here, we report clinico-pathological and molecular characteristics of four new cases of NRG1 fusion-positive lung adenocarcinoma treated with afatinib. Afatinib activity is reported.

      Result

      Case 1 is a 70-year-old, female, never-smoker, diagnosed with pan-wildtype, non-mucinous, adenocarcinoma. She received afatinib in the fifteenth-line setting and experienced a partial response (PR) for 24 months. Following further progression on chemotherapy, NRG1-fusion was identified using NanoString analysis (re-biopsy was performed to find an explanation for afatinib efficacy). The patient was re-challenged with afatinib (best response: PR [3 months]), before switching to atezolizumab (best response: progressive disease).

      Case 2 is a 66-year-old female, never-smoker, diagnosed with metastatic, non-mucinous adenocarcinoma. A CD74-NRG1 fusion was identified by Oncomine™ Comprehensive Assay, and fifth-line afatinib treatment was initiated. She experienced a PR, ongoing after 14 months of treatment.

      Case 3 is a 68-year-old male diagnosed with lung adenocarcinoma. A SDC4-NRG1 fusion was subsequently identified using Next Generation Sequencing and the patient initiated second-line afatinib treatment. He achieved stable disease as best response, lasting for four months.

      Case 4 is a 43-year-old, female, non-smoker, diagnosed with advanced invasive mucinous adenocarcinoma. A CD74-NRG1 fusion was subsequently identified by RNA sequencing and the patient initiated third-line afatinib treatment; PR is ongoing.

      Conclusion

      These findings add to a growing body of evidence suggesting afatinib activity in NRG1-fusion positive NSCLC. Prospective study of a larger cohort of patients with NRG1-fusion positive NSCLC treated with afatinib is warranted to better evaluate this potential activity.

      Patient

      Tumor type

      NRG1 fusion partner

      Best response

      Duration of response (months)

      Reference

      i

      Non-mucinous lung adenocarcinoma

      SLC3A2

      PR

      12

      Gay, et al. J Thoracic Oncol 2017

      ii

      IMA

      CD74

      PR

      10

      Gay, et al. J Thoracic Oncol 2017

      iii

      Non-mucinous lung adenocarcinoma

      SDC4

      PR

      12

      Jones, et al. Ann Oncol 2017

      iv

      IMA

      CD74

      PR

      6.5

      Cheema, et al. J Thoracic Oncol 2017

      v

      IMA

      CD74

      SD

      3

      Drilon, et al. Cancer Discov 2018

      vi

      IMA

      SDC4

      PD

      -

      Drilon, et al. Cancer Discov 2018

      vii

      IMA

      CD74

      PD

      -

      Drilon, et al. Cancer Discov 2018

      IMA, invasive mucinous lung adenocarcinoma; PD, progressive disease; SD, stable disease

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-53 - High MET Overexpression Does Not Predict the Presence of MET Exon 14 Splice Mutations in NSCLC: Results from the IFCT Predict.amm Study (ID 2324)

      10:15 - 18:15  |  Author(s): Jacques Cadranel

      • Abstract
      • Slides

      Background

      MET exon 14 splice site (METex14) mutations were recently described in Non Small Cell Lung Cancer (NSCLC) and reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations make them hard to detect by DNA sequencing in clinical practice. Because METex14 mutations induce increased stabilization of the MET receptor, it is anticipated that these mutations are associated with MET overexpression. We aim to determine whether NSCLC with high MET overexpression could define a subset of patients with a high rate of METex14 mutations.

      Method

      From the IFCT Predict.amm cohort of 843 consecutive patients with a treatment-naïve advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry (IHC) score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next generation sequencing (NGS). MET copy number analysis was also derived from the sequencing data.

      Result

      METex14 mutations were detected in two patients (2.2%) who also displayed a TP53 mutation and a PIK3CA mutation, respectively. A MET gene copy number increase was observed in 7 additional patients (7.7%). NGS analysis revealed inactivating mutations in TP53 (52.7%) and PTEN (1.1%) and oncogenic mutations in KRAS (28.6%), EGFR (7.7%), PIK3CA (4.4%), BRAF (4.4%), NRAS (2.2%), GNAS (1.1%) and IDH1 (1.1%).

      Conclusion

      The rate of METex14 mutations in NSCLC with high MET overexpression was similar to that found in unselected NSCLC. Moreover, we observed a high frequency of driver alterations in other oncogenes. Consequently these findings do not support the use of MET IHC as a surrogate marker for METex14 mutations.

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