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Non–Small-Cell Lung Cancer with HER2 Exon 20 Mutation: Regression with Dual HER2 Inhibition and Anti-VEGF Combination Treatment

      Advances in cancer genome sequencing technologies have led to the identification of non–small-cell lung cancer (NSCLC) subtypes having distinct potentially actionable molecular drivers, including mutations in the kinase domain of human epidermal growth factor receptor-2 (HER2), which have been reported in approximately 4% of NSCLC cases.
      • Stephens P
      • Hunter C
      • Bignell G
      • et al.
      Lung cancer: intragenic ERBB2 kinase mutations in tumours.
      Preclinical and clinical studies demonstrated that HER2 mutations in NSCLC are associated with a favorable response to HER2 targeted therapies.
      • Wang SE
      • Narasanna A
      • Perez-Torres M
      • et al.
      HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors.
      ,
      • Cappuzzo F
      • Bemis L
      • Varella-Garcia M
      HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer.

      CASE STUDY

      We report a case study of a 53-year-old woman with lung adenocarcinoma and an HER2 exon 20 mutation (insertion 774–775 AYVM) metastatic to the brain and right lung, who was treated with the HER2 tyrosine kinase inhibitor lapatinib, anti-HER2 monoclonal antibody trastuzumab, and antivascular endothelial growth factor antibody bevacizumab. The patient was previously treated with two lines of systemic chemotherapy (cisplatin with docetaxel; carboplatin with pemetrexed) with stable disease as the best response and CyberKnife stereotactic radiotherapy to the brain.
      Sequenom MassARRAY analysis of the primary tumor performed in a Clinical Laboratory Improvement Amendments–certified laboratory showed a HER2 exon 20 mutation (insertion 774–775 AYVM) with no other mutations in an additional 52 tested oncogenes.
      In October 2011, after signing informed consent, the patient received therapy on a protocol approved by the M.D. Anderson Institutional Review Board (NCT00543504) with a combination of lapatinib, trastuzumab, and bevacizumab. Her baseline computed tomography (CT) of chest, abdomen, and pelvis revealed metastatic lesions in the right lung, and a magnetic resonance imaging (MRI) of brain showed a treated lesion in the ventral pons and a new small right parietal metastasis.
      The first restaging with CT of chest, abdomen, pelvis, and MRI brain after 6 weeks (2 cycles) of treatment showed marked improvement in both brain metastases and no change in size in the right lung lesions per Response Evaluation Criteria in Solid Tumors 1.0; however, some of the lung lesions demonstrated cavitation (Fig. 1). The patient continues to be on therapy for more than 7 months, and CT of chest, abdomen, pelvis and MRI of the brain, demonstrate continuing improvement with complete cavitation in the right lung lesion (Fig. 1). Treatment-related side effects were manageable.
      Figure thumbnail gr1
      FIGURE 1Computed tomography of the right lung lesion at baseline, 6 weeks, and after 27 weeks of treatment.

      DISCUSSION

      It is plausible that the salutary effect observed in our patient was enhanced by dual HER2 inhibition. Emerging evidence suggests that dual targeting of epidermal growth factor receptor (EGFR) with an antibody and tyrosine kinase inhibitor may be effective in cancers, at least partially driven by EGFR, and can target both kinase-dependent and kinase-independent functions.
      • Weickhardt AJ
      • Price TJ
      • Chong G
      • et al.
      Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer.
      ,
      • Weihua Z
      • Tsan R
      • Huang WC
      • et al.
      Survival of cancer cells is maintained by EGFR independent of its kinase activity.
      In addition, lapatinib and trastuzumab were combined with bevacizumab, which has known activity in NSCLC and could have contributed further to the therapeutic response.
      In conclusion, we observed that a heavily pretreated patient with advanced NSCLC, harboring a HER2 exon 20 mutation, attained impressive and durable antitumor activity to dual HER2 inhibition in combination with bevacizumab. This supports previous anecdotal reports and suggests that using HER2-inhibiting strategies warrants further investigation in patients with NSCLC and HER2 mutations.

      ACKNOWLEDGMENTS

      Supported by grant number RR024148 from the National Center for Research Resources, a component of the NIH Roadmap for Medical Research (http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp). All treatment regimens given and data analyses were performed in accordance with M.D. Anderson Institutional Review Board guidelines. We thank Jenny Jiang for clinical trial coordination and Joann Aaron for scientific review and editing of this article.

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        Lung cancer: intragenic ERBB2 kinase mutations in tumours.
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        HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer.
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