CHK1 Inhibitor. Prexasertib, LY MsOH H 2 O. Drug Discovery Platform: Cancer Cell Signaling

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1 CHK1 Inhibitor Prexasertib, LY MsOH H 2 O Derived from Garrett MD and Collins I 1 ; Thompson R and Eastman A. 2 Drug Discovery Platform: Cancer Cell Signaling

2 A Phase 2 Study of LY in Patients With Extensive-Stage Disease Small Cell Lung Cancer* Extensive-stage disease small cell lung cancer (ED-SCLC) and received a prior platinum-based regimen Received more than two prior therapies for ED-SCLC (including immunotherapy, targeted therapies, or chemotherapy) - Cohort 1: Must have had an objective response to prior platinum-based therapy with subsequent progression 90 days after the last dose of platinum - Cohort 2: Must have either not had an objective response to prior platinum-based therapy or had progression <90 days after the last dose of platinum Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Patients with ED-SCLC who have either platinum-sensitive or platinum-resistant/ refractory disease Symptomatic central nervous system malignancy or metastasis Serious cardiac condition Please visit for more information on this clinical trial [NCT ]. Patients with platinum-sensitive disease Patients with platinum-resistant/ refractory disease * This clinical trial is being conducted globally. Objective response rate in patients with platinum-sensitive ED-SCLC Objective response rate in patients with platinum-resistant/ refractory ED-SCLC 2 3

3 A Phase 1b Trial of LY in Combination With Chemotherapy or Targeted Agents in Advanced and/or Metastatic Tumors* For all parts except part B dose expansion: A diagnosis of cancer that is advanced or metastatic Taken an unapproved drug as treatment for any indication within the last 28 days prior to starting study treatment For part B dose expansion: Confirmed KRAS wild-type colorectal cancer (CRC) that is metastatic or recurrent and has failed oxaliplatin- and irinotecan-based chemotherapy or must be intolerant of irinotecan or oxaliplatin Must be, in the judgment of the investigator, an appropriate candidate for experimental therapy after available standard therapies have failed Adequate organ function Discontinuation of all previous systemic treatments for cancer and recovery from the acute effects of therapy. Participants must have discontinued mitomycin C or nitrosourea therapy at least 42 days, and have discontinued any cytotoxic therapies at least 28 days, prior to study enrollment. Radiation therapy and surgery must be completed at least 4 weeks before study enrollment Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 3 months following the last dose of study drug. Females with childbearing potential must have a negative serum or urine pregnancy test within 14 days of the first dose of study drug and must not be breast-feeding Active symptomatic fungal, bacterial, or viral infection, including HIV or hepatitis A, B, or C Serious heart condition, such as congestive heart failure, unstable angina pectoris, or heart attack within the last 3 months Family history of long QTc syndrome Serotonin-secreting carcinoid tumor or a prior history of drug-induced serotonin syndrome Acute leukemia Please visit for more information on this clinical trial [NCT ]. * This clinical trial is being conducted in the United States. Part A: Dose escalation of cisplatin + prexasertib with or without prophylactic G-CSF followed by dose expansion of recommended part A dose and schedule in participants with advanced and/or metastatic disease Part B: Dose escalation of cetuximab + prexasertib with or without prophylactic G-CSF followed by dose expansion of recommended part B dose in participants with CRC Part C: Dose escalation of pemetrexed + prexasertib followed by dose expansion of recommended part C dose in participants with advanced and/or metastatic disease Part D: Dose escalation of 5-FU + prexasertib followed by dose expansion of recommended part D dose in participants with advanced and/or metastatic disease Part E: Dose escalation of prexasertib + LY followed by dose expansion of recommended part E dose in participants with advanced and/or metastatic disease Safe and tolerable phase 2 dose of prexasertib in combination with cisplatin, cetuximab, pemetrexed, 5-FU, or LY

4 A Phase 1b Trial of LY in Combination With Chemoradiation in Patients With Locally Advanced Head and Neck Squamous Cell Cancer* Part A: Locally advanced head and neck squamous cell carcinoma of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls), hypopharynx, or larynx Taken an unapproved drug as treatment for any indication within the last 28 days prior to starting study treatment Must be able to comply with the treatment plan and follow-up schedule Any of the following prior therapies or treatments: Systemic therapy for the study cancer, radiation therapy to the head and neck region that overlaps with a prior radiation therapy field, or surgery with curative intent in the head and neck region for locally advanced disease Adequate organ function Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Participants of reproductive potential must agree to use medically approved contraceptive precautions during the study, and for 3 months following the last dose of study drug, and must not be breast-feeding Prexasertib + cisplatin + radiation Part B: Prexasertib + cetuximab + radiation Recommended phase 2 dose for parts A and B Evidence of a distant metastatic disease Active symptomatic fungal, bacterial, or viral infection, including HIV or hepatitis A, B, or C Serious heart condition, such as congestive heart failure, unstable angina pectoris, or heart attack within the last 3 months Family history of long QTc interval syndrome Known allergic reaction against any of the components of the study treatment Please visit for more information on this clinical trial [NCT ]. * This clinical trial is being conducted globally. 6 7

5 A Phase 1 Dose-Escalation Study of LY in Combination With Ralimetinib in Patients With Advanced or Metastatic Cancer* Advanced or metastatic cancer Evidence or history of central nervous system metastasis Part B: Colorectal cancer (CRC) or non-small cell lung cancer (NSCLC) with known KRAS and/or BRAF mutations Serious heart condition Discontinuation of all previous treatments for cancer and recovered from the acute effects from the therapy Disease that requires immunosuppressive medication Major small bowel resection that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy or inflammatory bowel disease Prior participation in a clinical trial with prexasertib or ralimetinib Part A: Dose escalation of prexasertib + ralimetinib in patients with solid tumors Part B1: Dose confirmation of prexasertib + ralimetinib in patients with known mutations in KRAS and/or BRAF (CRC) Part B2: Dose confirmation of prexasertib + ralimetinib in patients with known mutations in KRAS and/or BRAF (NSCLC) Please visit for more information on this clinical trial [NCT ]. * This clinical trial is being conducted globally. Determine recommended phase 2 dose of prexasertib in combination with ralimetinib 8 9

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7 Target Molecule Checkpoint kinase 1 (CHK1) is a global regulator of the mammalian cell cycle. In addition to regulating DNA damage checkpoints, CHK1 plays a central role in normal DNA replication, resolving replication stress, progression to mitosis, and cytokinesis. Inhibition of CHK1 in the absence of DNA damage can cause impaired DNA replication, loss of DNA damage checkpoints, premature entry into mitosis with highly fragmented DNA, and cell death via replication catastrophe.3 Prexasertib (LY monomesylate monohydrate) is a small molecule that in vitro preferentially binds to and inhibits CHK1 and, to a lesser extent, inhibits CHK2, thus inducing DNA double-strand breaks, a loss in checkpoint function, increased replication stress, and cell death.3 Clinical Development Prexasertib is being investigated in phase I clinical trials and in clinical trials in patients with head and neck cancer and small cell lung cancer. Study Schemas Not Available [NCT ] Early Development A Study of Prexasertib (LY ) in Japanese Participants With Advanced Cancers References: 1. Garrett MD, Collins I. Trends Pharmacol Sci. 2011;32(5): Thompson R, Eastman A. Br J Clin Pharmacol. 2013;76(3): King C, et al. Mol Cancer Ther. 2015;14(9): ON /2016 PRINTED IN USA Lilly USA, LLC All rights reserved.