Cohort D Xentuzumab + abemaciclib + fulvestrant (500 mg/month) Key exclusion criteria RP2D-4 NSCLC. Cohort F Xentuzumab + abemaciclib + fulvestrant

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1 A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2-negative breast cancer (plus endocrine therapy) Douglas Yee, 1 * Marie Paule Sablin, 2 Hiroji Iwata, 3 Erica L. Johnston, 4 Thomas Bogenrieder, 5 Josep Serra, 6 Hairui Hua, 7 Patricia Lo Russo, 8 Aleix Prat 9 San Antonio Breast Cancer Symposium - December 5-9, 2017 OT Masonic Cancer Center, University of Minnesota, Minnesota, MN, USA; 2 Institut Curie, Paris, France; 3 Aichi Cancer Center Hospital, Nagoya, Japan; 4 Eli Lilly and Company, Indianapolis, IN, USA; 5 Boehringer Ingelheim RCV, Vienna, Austria; 6 Boehringer Ingelheim España, S.A., Barcelona, Spain; 7 Boehringer Ingelheim (China) Investment Co., Ltd., Shanghai, China; 8 Yale Cancer Center, New Haven, Connecticut, CT, USA; 9 Hospital Clínic, Barcelona, Spain Introduction Trial Key points Unmet need for treatment options for HR+, HER2 breast cancer The majority of patients diagnosed with breast cancer present with HR+, HER2 tumors 1 For these patients endocrine therapy is the standard of care, however, acquired resistance is common, leading to disease progression and death 2 Alternative treatment options are needed to delay or prevent endocrine resistance and improve outcomes for patients with HR+, HER2 breast cancer Rationale for dual inhibition The IGF and the CDK4/6-retinoblastoma pathways have been implicated in the pathogenesis and resistance mechanisms of a variety of cancers, including HR+, HER2 breast cancer 3 6 Cyclin D binds to, and activates, CDK4 and 6, which phosphorylate Rb. Phosphorylated Rb disassociates from the transcription factor E2F, allowing transcription of the target genes responsible for progression through the G1/S checkpoint 7 (Figure 1) IGF-ligand-dependent signaling via the IGF receptor results in upregulation of cyclin D1, and thus, progression through the cell cycle via the above pathway Therefore, the simultaneous dual inhibition of IGF and CDK4/6 should lead to decreased cell proliferation through disruption of cell-cycle progression CDK, cyclin-dependent kinase; HR+, hormone receptor-positive: HER2, human epidermal growth factor receptor-2 negative: IGF, insulin-like growth factor; Rb, retinoblastoma protein. Study Design Prospective, open-label, non-randomized, multiple dose-finding, Phase Ib study, followed by expansion cohorts (NCT ) Dose finding Cohorts (A,B,C,D) Cohort B Xentuzumab + abemaciclib + letrozole (2.5 mg/day) Solid tumors Cohort A Xentuzumab (starting dose 1,000 mg weekly i.v.) + abemaciclib (starting dose 150 mg every 12 hours) Breast Cancer Cohort C Xentuzumab + abemaciclib + anastrozole (1 mg/day) RP2D-1 Cohort D Xentuzumab + abemaciclib + fulvestrant (500 mg/month) Key inclusion criteria: All cohorts 18 years ( 20 years in Japan) ECOG PS 0 1 Measurable/evaluable disease Adequate organ function Inclusion criteria: Breast cancer Cohorts B, C, D, F Histologically or cytologically confirmed advanced and/or metastatic breast cancer not amenable to resection or radiation HR+, HER2 disease Post-menopausal women Eligible for corresponding hormonal therapy Cohort F only: Disease refractory to aromatase inhibitor therapy and CDK4/6 inhibitor treatment Key exclusion criteria Objectives: MTD/RP2D of xentuzumab in combination with abemaciclib with hormonal therapy Anti-tumor activity of xentuzumab in combination with abemaciclib plus fulvestrant in patients with HR+, HER2 breast cancer Study design: Open-label, non-randomized, multiple dose-finding, Phase Ib study, followed by expansion cohorts Endpoints for breast cancer cohorts: Primary endpoints: MTD and the number of patients with DLTs (Cohorts B D); OR (Cohort F) Secondary endpoints (Cohort F): disease control; time to OR; duration of OR; duration of disease control; PFS Status: Currently enrolling in Japan, US, France and Spain Figure 1: Role of CDK4/6 and cyclin D in cell-cycle progression Abemaciclib M G2 G1 A small-molecule inhibitor of CDK4 and 6 Greater selectivity for CDK4 compared with CDK6 Inhibits Rb phosphorylation and leads to G1 arrest Abemaciclib has shown clinical activity in HR+ breast cancer, and other solid tumors 9,10 S E2F E2F Mechanism of action: xentuzumab and abemaciclib Xentuzumab A humanized IgG1 mab Binds with high affinity to IGF-1 and IGF-2 and potently neutralizes proliferative and pro-survival cellular signaling triggered by both proteins 8 IR, insulin receptor; mab, monoclonal antibody IGF-1R IGF-1 Rb Rb Growth, proliferation, survival P CDK4 CDK6 Progression through the cell cycle IGF-2 E2F Rb IGF-2 P IR-A Cyclin D Cyclin D Xentuzumab neutralizes IGF-1 and IGF-2 IGF-1R CDK4 Abemaciclib CDK6 Cyclin D Cyclin D IR-A RP2D-2 Expansion Cohorts (E,F) RP2D-3 NSCLC, non-small cell lung cancer; RP2D, recommended Phase 2 dose RP2D-4 Cohort F Xentuzumab + abemaciclib + fulvestrant Objectives for breast cancer cohorts Cohorts B, C, D (dose-finding cohorts) To determine the maximum tolerated dose (MTD)/RP2D of xentuzumab in combination with abemaciclib with hormonal therapy (letrozole, anastrozole, fulvestrant) Cohort F (expansion cohort) To assess the anti-tumor activity of the triplet combination of xentuzumab, abemaciclib and fulvestrant in patients with breast cancer who have progressed following aromatase inhibitor and CDK4/6 inhibitor treatment Endpoints for breast cancer cohorts Cohorts B, C, D Cohort F Primary endpoints MTD No. of patients with DLTs* OR (CR, PR) Disease control (CR, PR, SD ) Secondary endpoints Time to OR Duration of OR Exploratory biomarker analysis will also be performed Duration of disease control *During the MTD evaluation period (first 28-day cycle); According to RECIST 1.1; SD lasting 24 weeks * Per REIST 1.1. SD lasting at least 24 weeks CR, complete response; DLT, dose-limiting toxicity; OR, objective response; PFS, progression-free survival; PR, partial response; SD, stable disease NSCLC Cohort E Xentuzumab + abemaciclib PFS Active infection Symptomatic CNS metastases Severe or uncontrolled systemic disease Inadequate bone marrow or organ function Unresolved treatment-related toxicity from prior therapy >CTCAE grade 1* Patients with: Any other malignancy Pre-existing renal disease Hypersensitivity to study drugs (or similar compounds) Type I diabetes (or uncontrolled type II) Patients with baseline Grade 2 hyperglycemia or diarrhea Treatment within 21 days and/or 3 half-lives for immunotherapy Chemotherapy Androgens IGF-1R targeting compounds Anti-CDK agents (except Cohort F) Biological or radiation therapy Previous treatments Any investigational drug Thalidomide Major surgery <28 days prior Erythropoietin, G-CSF, and GM-CSF within 2 weeks prior to study Radiotherapy to 25% of bone marrow *Except for stable sensory neuropathy CTCAE grade 2 and alopecia CNS, central nervous system; CTCAE, Common Terminology Criteria for Adverse Events; ECOG PS, Eastern Cooperative Oncology Group performance status; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor Current status Patient screening started in May 2017 Cohort A completed enrollment in November 2017 Recruitment is ongoing in Japan, US, France and Spain Target enrollment is ~88 patients, including ~56 patients with advanced HR+, HER2 breast cancer, of whom ~20 had previously been treated with CDK4/6 inhibitors 1. Howlader N et al. J Natl Cancer Inst 2014;106(5) 2. Cardoso F et al. Ann Oncol 2012;23 Suppl 7:vii Fidler MJ, et al. Ther Adv Med Oncol 2012;4: Pollak M. Nat Rev Cancer 2012;12: Hamilton E, Infante JR. Cancer Treat Rev 2016;45: Spring L, et al. Discov Med 2016;21:65 74 References 7. Weinberg RA. Cell 1995;81: Friedbichler K, et al. Mol Cancer Ther 2014;13: Patnaik A, et al. Cancer Discov 2016;6: Dickler MN, et al. Clin Cancer Res 2017;23(17): Scan the QR code for an electronic copy of the poster and supplementary content This study was funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of poster development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Christina Jennings, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster. *This presentation is the intellectual property of the author/presenter. Contact them at yeexx006@umn.edu for permission to reprint and/or distribute; Materials available via QR (Quick Response) are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions.

2 A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2-negative breast cancer (plus endocrine therapy) Douglas Yee, 1 * Marie Paule Sablin, 2 Hiroji Iwata, 3 Erica L. Johnston, 4 Thomas Bogenrieder, 5 Josep Serra, 6 Hairui Hua, 7 Patricia Lo Russo, 8 Aleix Prat 9 1 Masonic Cancer Center, University of Minnesota, Minnesota, MN, USA; 2 Institut Curie, Paris, France; 3 Aichi Cancer Center Hospital, Nagoya, Japan; 4 Eli Lilly and Company, Indianapolis, IN, USA; 5 Boehringer Ingelheim RCV, Vienna, Austria; 6 Boehringer Ingelheim España, S.A., Barcelona, Spain; 7 Boehringer Ingelheim (China) Investment Co., Ltd., Shanghai, China; 8 Yale Cancer Center, New Haven, Connecticut, CT, USA; 9 Hospital Clínic, Barcelona, Spain San Antonio Breast Cancer Symposium. *yeexx006@umn.edu

3 Introduction Unmet need for treatment options for HR+, HER2 breast cancer The majority of patients diagnosed with breast cancer present with HR+, HER2 tumors 1 For these patients endocrine therapy is the standard of care, however, acquired resistance is common, leading to disease progression and death 2 Alternative treatment options are needed to delay or prevent endocrine resistance and improve outcomes for patients with HR+, HER2 breast cancer HR+, hormone receptor-positive: HER2, human epidermal growth factor receptor-2 negative.

4 Introduction (cont d) Rationale for dual inhibition The IGF and the CDK4/6-retinoblastoma pathways have been implicated in the pathogenesis and resistance mechanisms of a variety of cancers, including HR+, HER2 breast cancer 3 6 Cyclin D binds to, and activates, CDK4 and 6, which phosphorylate Rb. Phosphorylated Rb disassociates from the transcription factor E2F, allowing transcription of the target genes responsible for progression through the G1/S checkpoint 7 (Figure 1) IGF-ligand-dependent signaling via the IGF receptor results in upregulation of cyclin D1, and thus, progression through the cell cycle via the above pathway Therefore, the simultaneous dual inhibition of IGF and CDK4/6 should lead to decreased cell proliferation through disruption of cell-cycle progression CDK, cyclin-dependent kinase; IGF, insulin-like growth factor; Rb, retinoblastoma protein.

5 Introduction (cont d) Figure 1: Role of CDK4/6 and cyclin D in cell-cycle progression M G1 Rb P CDK4 Cyclin D E2F CDK6 Cyclin D G2 S E2F Rb P Progression through the cell cycle

6 Introduction (cont d) Mechanism of action: xentuzumab A humanized IgG1 mab Binds with high affinity to IGF-1 and IGF-2 and potently neutralizes proliferative and pro-survival cellular signaling triggered by both proteins 8 Xentuzumab neutralizes IGF-1 and IGF-2 IGF-1 IGF-2 IGF-2 IGF-1R IR-A IGF-1R IR-A Growth, proliferation, survival IR, insulin receptor; mab, monoclonal antibody

7 Introduction (cont d) Mechanism of action: abemaciclib A small-molecule inhibitor of CDK4 and 6 Greater selectivity for CDK4 compared with CDK6 Inhibits Rb phosphorylation and leads to G1 arrest Abemaciclib has shown clinical activity in HR+ breast cancer, and other solid tumors 9,10 CDK4 Cyclin D E2F Rb Abemaciclib CDK6 Cyclin D

8 Trial Study Design Prospective, open-label, non-randomized, multiple dose-finding, Phase Ib study, followed by expansion cohorts (NCT ) Dose finding Cohorts (A,B,C,D) Solid tumors Cohort A Xentuzumab (starting dose 1,000 mg weekly i.v.) + abemaciclib (starting dose 150 mg every 12 hours) RP2D-1 Breast Cancer Cohort B Xentuzumab + abemaciclib + letrozole (2.5 mg/day) Cohort C Xentuzumab + abemaciclib + anastrozole (1 mg/day) Cohort D Xentuzumab + abemaciclib + fulvestrant (500 mg/month) RP2D-2 RP2D-3 RP2D-4 Expansion Cohorts (E,F) NSCLC, non-small cell lung cancer; RP2D, recommended Phase 2 dose Cohort F Xentuzumab + abemaciclib + fulvestrant NSCLC Cohort E Xentuzumab + abemaciclib

9 Trial (cont d) Objectives for breast cancer cohorts Cohorts B, C, D (dose-finding cohorts) To determine the maximum tolerated dose (MTD)/RP2D of xentuzumab in combination with abemaciclib with hormonal therapy (letrozole, anastrozole, fulvestrant) Cohort F (expansion cohort) To assess the anti-tumor activity of the triplet combination of xentuzumab, abemaciclib and fulvestrant in patients with breast cancer who have progressed following aromatase inhibitor and CDK4/6 inhibitor treatment

10 Trial (cont d) Endpoints for breast cancer cohorts Primary endpoints Secondary endpoints Cohorts B, C, D MTD No. of patients with DLTs* Cohort F OR (CR, PR) Disease control (CR, PR, SD ) Time to OR Duration of OR Duration of disease control PFS Exploratory biomarker analysis will also be performed *During the MTD evaluation period (first 28-day cycle); According to RECIST 1.1; SD lasting 24 weeks CR, complete response; DLT, dose-limiting toxicity; OR, objective response; PFS, progression-free survival; PR, partial response; SD, stable disease

11 Trial (cont d) Key inclusion criteria: All cohorts 18 years ( 20 years in Japan) ECOG PS 0 1 Measurable/evaluable disease Adequate organ function Inclusion criteria: breast cancer Cohorts B, C, D, F Histologically or cytologically confirmed advanced and/or metastatic breast cancer not amenable to resection or radiation HR+, HER2 disease Post-menopausal women Eligible for corresponding hormonal therapy Cohort F only: Disease refractory to aromatase inhibitor therapy and CDK4/6 inhibitor treatment ECOG PS, Eastern Cooperative Oncology Group performance status

12 Trial (cont d) Key exclusion criteria Patients with: Active infection Symptomatic CNS metastases Severe or uncontrolled systemic disease Inadequate bone marrow or organ function Unresolved treatment-related toxicity from prior therapy >CTCAE grade 1* Any other malignancy Pre-existing renal disease Hypersensitivity to study drugs (or similar compounds) Type I diabetes (or uncontrolled type II) Patients with baseline Grade 2 hyperglycemia or diarrhea *Except for stable sensory neuropathy CTCAE grade 2 and alopecia CNS, central nervous system; CTCAE, Common Terminology Criteria for Adverse Events

13 Trial (cont d) Key exclusion criteria Treatment within 21 days and/or 3 half-lives for immunotherapy Chemotherapy Any investigational drug Biological or radiation therapy Androgens Thalidomide

14 Trial (cont d) Key exclusion criteria IGF-1R targeting compounds Previous treatments Major surgery <28 days prior Erythropoietin, G-CSF, and GM-CSF within 2 weeks prior to study Anti-CDK agents (except Cohort F) Radiotherapy to 25% of bone marrow G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor

15 Current status Patient screening started in May 2017 Cohort A completed enrollment in November 2017 Recruitment is ongoing in Japan, US, France and Spain Target enrollment is ~88 patients, including ~56 patients with advanced HR+, HER2 breast cancer, of whom ~20 had previously been treated with CDK4/6 inhibitors

16 Key points Objectives: MTD/RP2D of xentuzumab in combination with abemaciclib with hormonal therapy Anti-tumor activity of xentuzumab in combination with abemaciclib plus fulvestrant in patients with HR+, HER2 breast cancer Study design: Open-label, non-randomized, multiple dose-finding, Phase Ib study, followed by expansion cohorts Endpoints for breast cancer cohorts: Primary endpoints: MTD and the number of patients with DLTs (Cohorts B D); OR (Cohort F) Secondary endpoints (Cohort F): disease control; time to OR; duration of OR; duration of disease control; PFS Status: Currently enrolling in Japan, US, France and Spain

17 References 1. Howlader N et al. J Natl Cancer Inst 2014;106(5) 2. Cardoso F et al. Ann Oncol 2012;23 Suppl 7:vii Fidler MJ, et al. Ther Adv Med Oncol 2012;4: Pollak M. Nat Rev Cancer 2012;12: Hamilton E, Infante JR. Cancer Treat Rev 2016;45: Spring L, et al. Discov Med 2016;21: Weinberg RA. Cell 1995;81: Friedbichler K, et al. Mol Cancer Ther 2014;13: Patnaik A, et al. Cancer Discov 2016;6: Dickler MN, et al. Clin Cancer Res 2017;23(17):

18 Acknowledgements This study was funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of poster development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Christina Jennings, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster. This presentation is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute.