ERBB2-Mutated Metastatic Non–Small Cell Lung Cancer: Response and Resistance to Targeted Therapies Jody C. Chuang, MD, PhD, Henning Stehr, PhD, Ying.

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ERBB2-Mutated Metastatic Non–Small Cell Lung Cancer: Response and Resistance to Targeted Therapies Jody C. Chuang, MD, PhD, Henning Stehr, PhD, Ying Liang, MD, PhD, Millie Das, MD, Jane Huang, MD, Maximilian Diehn, MD, PhD, Heather A. Wakelee, MD, Joel W. Neal, MD, PhD Journal of Thoracic Oncology Volume 12, Issue 5, Pages 833-842 (May 2017) DOI: 10.1016/j.jtho.2017.01.023 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Examples of best responses during erb-b2 receptor tyrosine kinase 2 (HER2)-directed therapies. (A) Patient 1 at the beginning of therapy (left) and 5 months after the start of vinorelbine and trastuzumab therapy (right). (B) Patient 2 at the beginning of therapy (left) and 3.5 months after the start of vinorelbine and trastuzumab therapy (right). (C) Patient 3 at the beginning of therapy (left) and 2 months after the start of vinorelbine and trastuzumab therapy (right). (D) Patient 4 at the beginning of therapy (left) and 2 months after the start of afatinib therapy (right). (E) Patient 4 at the beginning of therapy (left) and 3.5 months after the start of vinorelbine and trastuzumab therapy (right). (F) Patient 4 at the beginning of therapy (left) and 1 month after the start of afatinib and bevacizumab (right). Journal of Thoracic Oncology 2017 12, 833-842DOI: (10.1016/j.jtho.2017.01.023) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Swimmer plot of responses to various therapies in the responders: carboplatin/gemcitabine/bevacizumab followed by gemcitabine/bevacizumab maintenance (A), docetaxel (B), pemetrexed (C), irinotecan (D), rastuzumab/vinorelbine (E), carboplatin/pemetrexed followed by pemetrexed maintenance (F), trastuzumab/docetaxel (G), carboplatin/docetaxel/bevacizumab plus investigational anti–mesenchymal-epithelial transition agent (H), carboplatin/pemetrexed/bevacizumab followed by pemetrexed/bevacizumab maintenance (I), erlotinib (J), afatinib (K), ado-trastuzumab (L), nivolumab (M), etirinotecan pegol (N), and afatinib/bevacizumab (O). Journal of Thoracic Oncology 2017 12, 833-842DOI: (10.1016/j.jtho.2017.01.023) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Erb-b2 receptor tyrosine kinase 2 gene (ERBB2/HER2) copy number gain as a putative resistance mechanism to afatinib. Serial circulating tumor DNA (ctDNA) measurements from patient 4. The panel displays ctDNA content, the ERBB2 exon 20 insertion allele fraction, and the copy number of ERBB2 and EGFR normalized by percentage of ctDNA (based on a heterozygous mutation in protocadherin 10 gene [PCDH10] observed in all samples). Panel displays alterations in EGFR detected in plasma. ND, not detected. Journal of Thoracic Oncology 2017 12, 833-842DOI: (10.1016/j.jtho.2017.01.023) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions