Pathway Targeted Immunotherapy: Rationale and Evidence of Durable Clinical Responses with a Novel, EGF-directed Agent for Advanced NSCLC Rafael Rosell,

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Pathway Targeted Immunotherapy: Rationale and Evidence of Durable Clinical Responses with a Novel, EGF-directed Agent for Advanced NSCLC Rafael Rosell, PhD, Elia Neninger, MD, Marianne Nicolson, MD, Rudolf M. Huber, MD, PhD, Sumitra Thongprasert, PhD, Purvish M. Parikh, MD, PhD, Erik D’Hondt, PhD Journal of Thoracic Oncology Volume 11, Issue 11, Pages 1954-1961 (November 2016) DOI: 10.1016/j.jtho.2016.08.132 Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 (A) Data from an A549 cell line with wild-type EGFR and G12S KRAS mutation. The first column in the bar graph shows the phosphorylation status of resting cells, the second column reflects the status after the addition of epidermal growth factor (EGF), and the subsequent columns the effect of adding anti-EGF at increasing concentrations. (B) Data obtained in the H2228 cell line in which EGFR and KRAS are wild-type but there is an EML4-ALK translocation. As in A549 cells, the anti-EGF agent induces dose-dependent inhibition of phosphorylation, which, at the highest concentration, becomes nondetectable. (C) Data show the effect of anti-EGF in PC9 cells, which are EGFR-mutated (exon 19 deletion). Despite the EGFR mutation, there is again dose-dependent inhibition, although to a lesser extent than was seen in EGFR wild-type lines.8 Journal of Thoracic Oncology 2016 11, 1954-1961DOI: (10.1016/j.jtho.2016.08.132) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 The kinetics of antibody response (left scale). Titers rise rapidly after immunization and are maintained at a high level relative to baseline over more than a year. Over a similar time course, epidermal growth factor (EGF) concentration in serum falls (right scale) and remains low.9 Journal of Thoracic Oncology 2016 11, 1954-1961DOI: (10.1016/j.jtho.2016.08.132) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Survival (SV) in immunized versus control patients with baseline epidermal growth factor levels more than 250 pg/mL in the phase IIb study.11 CI, Confidence interval; HR, hazard ratio. Journal of Thoracic Oncology 2016 11, 1954-1961DOI: (10.1016/j.jtho.2016.08.132) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Computed tomography scan images from a 57-year-old man with stage T2N3M1 disease (A) pretreatment, (B) after 4 weeks of cisplatin and vinblastine doublet therapy, and (C) after 8 years of epidermal growth factor pathway targeted immunotherapy treatment. Images show total disappearance of the posterior mass in both lungs and reduction of parahilar tumor with opening of the left principal bronchus at 4 weeks, with response maintained at 8 years. Journal of Thoracic Oncology 2016 11, 1954-1961DOI: (10.1016/j.jtho.2016.08.132) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions