Prud’homme GJ1; Flavell RA, et al 2

TGFβR1 Kinase InhibitorGalunisertib, LY2157299 H20

Drug Discovery Platform: Cancer Angiogenesis and Tumor Microenvironment/Immuno-Oncology

The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

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A Phase 1b/2 Dose-Escalation and Cohort-Expansion Study of the Safety, Tolerability, and Efficacy of a Novel Transforming Growth Factor-Beta Receptor I Kinase Inhibitor (Galunisertib) Administered in Combination With Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors (Phase 1b) and in Recurrent or Refractory Non-small Cell Lung Cancer, Hepatocellular Carcinoma, or Glioblastoma (Phase 2)*

Key Inclusion Criteria• For phase 1b: Must have advanced refractory solid tumors in any line of therapy

• For phase 2:

- Recurrent or refractory non-small cell lung cancer (NSCLC; any histology), hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein ≥200 ng/mL, or glioblastoma (primary)

- Disease progression or was refractory or intolerant to one prior line of therapy and has refused currently approved second-line therapy

• For NSCLC: Prior lines of therapy must include a platinum-based therapy

• For HCC:

- Received one prior line of therapy with sorafenib or has progressed or been intolerant to sorafenib for participants not eligible for transarterial chemoembolization

- Child-Pugh class A only

- Participants may have any viral status (hepatitis B, C, or none) with a viral load <100 IU/mL

- Participants with hepatitis B must be on a nucleoside analog reverse transcriptase inhibitor

• For glioblastoma (GB): Previous first-line therapy with at least radiotherapy and temozolomide, except for participants with O6-methylguanine-DNA methyltransferase (MGMT) unmethylated newly diagnosed GB. Participants with MGMT unmethylated newly diagnosed GB may have received radiation therapy only

• Adequate organ function

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Key Exclusion Criteria• History of a serious cardiac condition within 6 months prior to enrollment,

such as unstable angina pectoris, congestive heart failure New York Heart Association class 3/4, or uncontrolled hypertension

• Documented major electrocardiogram abnormalities (not responding to medical treatments)

• Echocardiogram abnormalities, such as heart valve function defect

• Conditions consistent with predisposition for aneurysms

• Evidence of interstitial lung disease or active, noninfectious pneumonitis

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02423343].* This clinical trial is being conducted globally in partnership with Bristol-Myers Squibb.

Phase 1b

Phase 2

Dose escalation of galunisertib + nivolumab†

Galunisertib + nivolumab (NSCLC, HCC, or glioblastoma)‡§

Primary endpoint:Safety and tolerability of galunisertib

in combination with nivolumab

Primary endpoint:Safety of combination therapy

† Galunisertib is administered PO BID for the first 14 days of a 28-day cycle. Nivolumab is administered intravenously (IV) every 2 weeks for two cycles.

‡ Galunisertib is administered PO BID for the first 14 days of a 28-day cycle. Nivolumab is administered IV every 2 weeks of a 28-day cycle.

§ Participants continue study treatment until discontinuation criteria are met.

TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H2O

The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

4 5

TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H2O

A Phase 1b Dose-Escalation and Cohort-Expansion Study of the Safety, Tolerability, and Efficacy of a Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor (Galunisertib) Administered in Combination With the Anti-PD-L1 Antibody Durvalumab (MEDI4736) in Recurrent or Refractory Metastatic Pancreatic Cancer*

Key Inclusion Criteria• Recurrent metastatic pancreatic adenocarcinoma

• Disease progression, or refractory or intolerant to no more than two prior systemic regimens for locally advanced or metastatic pancreatic cancer

• Participants who have received prior neoadjuvant therapy and who now have metastatic disease must have received one of the following regimens for their metastatic disease prior to enrollment in this study:

- FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin)

- Nab-paclitaxel/gemcitabine

- TS-1 (tegafur gimeracil oteracil potassium)

- Liposomal irinotecan/5-fluorouracil/leucovorin

- Single-agent gemcitabine

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Key Exclusion Criteria• History of a serious cardiac condition within 6 months prior to enrollment (eg,

unstable angina pectoris, congestive heart failure New York Heart Association class 3/4, or uncontrolled hypertension)

• Electrocardiogram abnormalities (eg, cardiac arrhythmia, left bundle-branch block, or myocardial infarction within 6 months prior to enrollment)

• Echocardiogram abnormalities (eg, heart valve function defect or aneurysm)

• Conditions consistent with predisposition to aneurysms

• Interstitial lung disease or active, noninfectious pneumonitis

• Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA4 antibody, or small molecules specifically targeting T-cell co-stimulation or checkpoint pathways (eg, CD137, GITR, TIM-3, and LAG CAR-T cells and vaccines) within 6 months prior to starting study treatment

• Prior treatment with a TGFβR1 kinase inhibitor

• Prior therapy with a monoclonal antibody within 28 days prior to starting study treatment or not recovered (grade ≤1 at baseline) from adverse events (except for fatigue or alopecia) due to agents administered more than 28 days earlier

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02734160].* This clinical trial is being conducted globally in partnership with AstraZeneca.

Part A

Part B

Dose escalation of galunisertib + durvalumab

Dose confirmation of galunisertib + durvalumab

(pancreatic cohort expansion)

Primary endpoint:Safety and tolerability of

galunisertib in combination with durvalumab

Primary endpoint:Safety of galunisertib in

combination with durvalumab in patients with metastatic

pancreatic cancer

The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

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TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H2O

TargetThe transforming growth factor β (TGFβ) signaling pathway is complex and results in tumor suppressor or tumor-promoting activity depending on the cellular context in which the pathway is active. As many cancers progress to more aggressive disease states, the tumor suppressor arm of TGFβ signaling is lost and, instead, tumor cells proliferate. In contrast, TGFβ overexpression in advanced disease enhances tumor growth, suppresses the immune system, and exacerbates invasive and metastatic tumor cell behavior.3 TGFβ worsens immunosuppression by inhibiting cytotoxic cells such as CD8+ CTLs and NK cells and enhancing suppressive immune cells called T regulatory cells and myeloid-derived suppressor cells.2

MoleculeGalunisertib (LY2157299 monohydrate) is a small molecule that has been shown in vitro to block TGFβ signaling.4-7

Clinical DevelopmentGalunisertib is being investigated in phase I clinical trials, including combination clinical trials in immuno-oncology, and in clinical trials in patients with hepatocellular carcinoma and pancreatic cancer.

References: 1. Prud’homme GJ. Lab Invest. 2007;87(11):1077-1091. 2. Flavell RA, et al. Nat Rev Immunol. 2010;10(8):554-567. 3. Ikushima H, Miyazono K. Nat Rev Cancer. 2010;10(6):415-424. 4. Yingling JM, et al. Proc Amer Assoc Cancer Res. 2006;47. Abstract 250. 5. Rodón J, et al. Invest New Drugs. 2015;33(2):357-370. 6. Maier A, et al. Cell Oncol (Dordr). 2015;38(2):131-144. 7. Herbertz S, et al. Drug Des Devel Ther. 2015;9:4479-4499.

Study Schemas Not Available[NCT01246986] Gastrointestinal Cancer A Study of LY2157299 in Participants With Hepatocellular Carcinoma

[NCT02178358] Gastrointestinal Cancer A Study of LY2157299 in Participants With Advanced Hepatocellular Carcinoma

[NCT02240433] Gastrointestinal Cancer A Study of LY2157299 in Participants With Unresectable Hepatocellular Cancer (HCC)

ON99511 02/2017 PRINTED IN USA © Lilly USA, LLC 2017. All rights reserved.

The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

TGFβR1 Kinase Inhibitor Galunisertib, LY2157299 H2O