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Abemaciclib LY2835219

CDK4 & 6 INHIBITOR Abemaciclib, LY2835219 | CDK4 & 6 INHIBITOR

Target Many human tumors acquire alterations, which can lead to the activation of cyclin-dependent kinases (CDKs). These alterations include mutations that directly activate CDK4 & 6, gene amplifications, which increase expression of various protein activators such as D-type cyclins, as well as genetic losses, which reduce expression of protein inhibitors such as p16. These various mechanisms as well as loss of retinoblastoma (Rb) can lead to an enhanced proliferative potential by decreasing dependency on external growth factors and mitogenic signaling pathways, which are required to stimulate growth under normal conditions.2,3

Molecule Abemaciclib (LY2835219) has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4 & 6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell-cycle arrest and inhibition of cell proliferation.4,5

Clinical Development Abemaciclib is being investigated in clinical trials in patients with breast cancer, non-small cell lung cancer, pediatric cancer, or prostate cancer.

References: 1. Shapiro GI. J Clin Oncol. 2006;24(11):1770-1783. 2. Kim JK, Diehl JA. J Cell Physiol. 2009;220(2):292-296. 3. Choi YJ, Anders L. Oncogene. 2014;33(15):1890-1903. 4. Dempsey JA, et al. AACR Annual Meeting; April 6-10, 2013; Washington, DC. Abstract LB122. 5. Gelbert LM, et al. Invest New Drugs. 2014;32(5):825-837.

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.

2 Shapiro GI1 3 Abemaciclib, LY2835219 | CDK4 & 6 INHIBITOR eMonarcHER Key Inclusion Criteria Key Exclusion Criteria

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Abemaciclib Plus Standard Adjuvant Endocrine • Confirmed hormone-receptor-positive (HR+), HER2-positive early • Breast cancer with disease recurrence or distant metastatic disease Therapy in Participants With High-Risk, Node-Positive, HR+, HER2+ Early Breast Cancer Who Have Completed Adjuvant breast cancer (EBC) in initial diagnostic tissue that is invasive and (including contralateral axillary lymph node), lymph node-negative without evidence of disease recurrence or distant metastases status, pathological complete response from any prior systemic HER2-Targeted Therapy* • Prior definitive surgery of the primary breast tumor(s) treatments for early breast cancer, or inflammatory breast cancer • Available tumor tissue from breast or lymph node • Previous breast cancer (except ipsilateral ductal carcinoma in situ [DCIS] treated by locoregional therapy alone ≥5 years prior to study enrollment; • Received a minimum of four cycles of chemotherapy in the neoadjuvant/ contralateral DCIS treated by locoregional therapy at any time) adjuvant setting per standard-of-care therapy • Other cancer being treated and/or not in complete remission within the • Completed at least 9 months and up to 1 year of standard HER2- Abemaciclib† + endocrine therapy‡ Placebo† + endocrine therapy‡ last 5 years (except appropriately treated nonmelanomatous skin cancer targeted therapy without evidence of disease recurrence (neoadjuvant/ or carcinoma in situ of cervix, bladder, or colon) adjuvant combined duration) • Females who are pregnant or lactating • Received one of the following eligible HER2-targeted adjuvant regimens AND be randomized within 12 weeks of completing the regimen: • History of venous thromboembolism - For participants treated with neoadjuvant therapy (chemotherapy with • Other serious medical conditions Primary endpoint: trastuzumab-based therapy): single-agent adjuvant ado-trastuzumab • Previously received treatment with: Invasive disease-free survival emtansine - Any CDK4 & 6 inhibitor - For participants not treated with neoadjuvant therapy: adjuvant - Prior adjuvant treatment with immunotherapy, tucatinib, neratinib, pertuzumab with trastuzumab investigational HER2-directed therapy, or trastuzumab deruxtecan for • High-risk disease, defined by one of the following: treatment of breast cancer - For participants treated with neoadjuvant therapy (as defined above), - Endocrine therapy (ET) (eg, tamoxifen, raloxifene, or aromatase pathologically detected axillary nodal disease in the surgical inhibitor) for breast cancer prevention (without diagnosis of breast specimen cancer) The safety and efficacy - For participants not treated with neoadjuvant therapy, axillary - Additional chemotherapy, anticancer ET, or HER2-targeted therapy node-positive disease meeting one of the following criteria: beyond standard-of-care therapy for breast cancer at study enrollment of the agents under • Pathological tumor involvement in at least four ipsilateral axillary - Bone-targeting agents prescribed as cancer-modifying treatment investigation have not been lymph nodes agent (treatment for prevention of osteoporosis is permitted) established. There is no • Pathological tumor involvement in one to three ipsilateral axillary guarantee that the agents will lymph node(s) and at least one of the following criteria: receive regulatory approval and - Histological grade 2 or grade 3 disease * This clinical trial is being conducted globally. - Primary invasive tumor size ≥5 cm determined pathologically become commercially available † Abemaciclib or placebo equivalent is administered PO BID on days 1-28 of a 28-day cycle. for the uses being investigated. ‡ Physician’s choice endocrine therapy is administered according to package label.

4 Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT04752332]. 5 Abemaciclib, LY2835219 | CDK4 & 6 INHIBITOR

CYCLONE 1 Key Inclusion Criteria Key Exclusion Criteria

A Phase 2 Study of Abemaciclib in Metastatic Castration-Resistant Prostate Cancer Patients • Metastatic prostate cancer documented by positive bone scan and/or • Previously received abemaciclib or any other CDK4 & 6 inhibitors Previously Treated With a Novel Hormonal Agent and Taxane-Based Chemotherapy* CT/MRI for soft tissue • Serious preexisting medical condition(s), including but not limited • Presence of at least one measurable lesion as defined by Response to interstitial lung disease, severe dyspnea at rest or requiring Evaluation Criteria in Solid Tumors (RECIST) version 1.1 oxygen therapy, history of major surgical resection involving the • Castrate levels of baseline serum testosterone (≤50 ng/dL) stomach or small bowel, preexisting Crohn’s disease or ulcerative colitis, or a preexisting chronic condition resulting in • Disease progression during continuous androgen deprivation therapy baseline ≥ grade 2 diarrhea documented by at least one of the following: • History of any of the following conditions within the last 12 months: - Sequence of at least two rising prostate-specific antigen values at Abemaciclib† syncope of cardiovascular etiology, ventricular arrhythmia of a minimum of 1-week intervals pathological origin (including but not limited to ventricular - Radiographic progression per RECIST 1.1 for soft tissue tachycardia and ventricular fibrillation), or sudden cardiac arrest and/or per Prostate Cancer Working Group 3 (PCWG3) for bone • Active systemic infections (ie, appearance of ≥2 new bone lesions) Primary endpoint: • Untreated spinal cord compression, evidence of spinal metastases • Previously received (in the metastatic hormone-sensitive prostate cancer Objective response rate with risk of spinal compression, or structurally unstable bone lesions [mHSPC], nonmetastatic castration-resistant prostate cancer [nmCRPC], suggesting impending fracture or metastatic castration-resistant prostate cancer [mCRPC] settings): • Confirmed or suspected brain metastasis - At least one novel androgen receptor-axis therapy with abiraterone acetate, apalutamide, darolutamide, or enzalutamide AND - Two taxane regimens with docetaxel and cabazitaxel • Previously received ≤3 prior systemic therapy regimens for mCRPC. GnRHa, first-generation antiandrogens (flutamide, nilutamide, or The safety and efficacy bicalutamide), DES (or other estrogens), corticosteroids, ketoconazole, and bone loss-prevention will not count as systemic of the agents under therapy regimens investigation have not been • Availability of metastatic tumor sample (fresh biopsy or recent established. There is no archival tissue) guarantee that the agents will • Adequate organ function receive regulatory approval and • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 become commercially available * This clinical trial is being conducted globally. for the uses being investigated. † Abemaciclib is administered PO Q12H.

6 Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT04408924]. 7 Abemaciclib, LY2835219 | CDK4 & 6 INHIBITOR

NCT04238819 Key Inclusion Criteria Key Exclusion Criteria

A Phase 1b Dose Escalation Study of Abemaciclib in Combination With Temozolomide and Irinotecan (Part A) and Abemaciclib in • ≤18 years of age at the time of study enrollment • Tumor containing known somatic or germline Rb mutation Combination With Temozolomide (Part B) in Pediatric and Young Adult Patients With Relapsed/Refractory Solid Tumors*† • Body weight ≥10 kg and body surface area ≥0.5 m2 (screening is not required for enrollment) • Any relapsed/refractory malignant solid tumor (excluding lymphoma), • Prior allogenic bone marrow or solid organ transplant including central nervous system tumors, that have progressed on • Live vaccination within 4 weeks prior to starting study treatment standard therapies and, in the judgment of the investigator, are • History of syncope of cardiovascular etiology, ventricular tachycardia, appropriate candidates for the experimental therapy combinations in ventricular fibrillation, or sudden cardiac arrest within the last the study 12 months Part A: Dose escalation of Part B: Dose escalation of • Lansky score ≥50 for participants ≤16 years of age, and Karnofsky score • Intolerability or hypersensitivity to any of the study treatments or abemaciclib‡ + irinotecan§ + temozolomide|| abemaciclib‡ + temozolomide|| ≥50 for participants >16 years of age its components • Discontinued all previous treatments for cancer or investigational • Diagnosed and/or treated additional malignancy within 3 years prior agents and recovered from acute effects to grade ≤1 at the time to enrollment that may affect the interpretation of results, with the of enrollment Part A: Dose expansion of Part B: Dose expansion of exception of curatively treated basal cell carcinoma of the skin, abemaciclib‡ + irinotecan§ + temozolomide|| abemaciclib‡ + temozolomide|| • Able to swallow squamous cell carcinoma of the skin, and/or curatively resected in • Adequate hematologic and organ function ≤14 days prior to first dose of situ cervical and/or breast cancers study drug • Pregnant or breastfeeding • Females of reproductive potential must have negative serum pregnancy • Active systemic infections or viral load test at baseline within 7 days prior to starting treatment Primary endpoints: • Serious and/or uncontrolled preexisting medical conditions that Number of participants with dose-limiting toxicities • Both female and male participants of reproductive potential must agree would preclude participation in this study and mean steady-state concentrations of abemaciclib to use highly effective contraceptive precautions (and avoid sperm • Prior treatment with drugs known to be strong inhibitors or inducers in combination with other anticancer agents donation for males) during the trial. For abemaciclib, females should of isoenzyme cytochrome P450 3A (CYP3A) or strong inhibitors of use contraception for at least 3 weeks following the last abemaciclib UGT1A1 if the treatment cannot be discontinued or switched to a dose (males have no restriction for contraceptive use following different medication at least 5 half-lives prior to starting study drug The safety and efficacy treatment with abemaciclib). For other study drugs, highly effective • Prior treatment with a CDK4 & 6 inhibitor of the agents under contraceptive precautions (and avoiding sperm donation) must be used according to their label • Current enrollment in any other clinical study involving an investigation have not been investigational product or nonapproved use of a drug or device • Life expectancy of at least 8 weeks and able to complete at least one established. There is no cycle of treatment • Prior experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer guarantee that the agents will * This clinical trial is being conducted globally. • Caregivers and participants willing to make themselves available for the receive regulatory approval and † Additional criteria not shown here may exist for individual parts of the study. duration of the trial • Part A only: Bowel obstruction ‡ Abemaciclib is administered PO. become commercially available § Irinotecan is administered intravenously. for the uses being investigated. || Temozolomide is administered PO.

8 Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT04238819]. 9 Abemaciclib, LY2835219 | CDK4 & 6 INHIBITOR

10 11 Active Trials Currently Not Enrolling

[NCT02057133] Breast Cancer [NCT02763566] Breast Cancer A Study of LY2835219 (Abemaciclib) in MONARCH plus: A Study of Abemaciclib Combination With Therapies for Breast Cancer (LY2835219) in Participants With Breast Cancer That Has Spread [NCT03155997] Breast Cancer [NCT02107703] Breast Cancer monarchE: Endocrine Therapy With or Without MONARCH 2: A Study of Abemaciclib Abemaciclib (LY2835219) Following Surgery in (LY2835219) Combined With Fulvestrant in Participants With Breast Cancer Women With Hormone-Receptor-Positive, HER2-Negative Breast Cancer [NCT03703466] Breast Cancer A Study of Abemaciclib (LY2835219) With and [NCT02246621] Breast Cancer Without Food in Participants With Metastatic MONARCH 3: A Study of Nonsteroidal Breast Cancer Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With [NCT02779751] Breast Cancer or Lung Cancer Breast Cancer A Study of Abemaciclib (LY2835219) in Participants With Non-small Cell Lung Cancer [NCT02675231] Breast Cancer or Breast Cancer monarcHER: A Study of Abemaciclib (LY2835219) in Women With HR+, HER2+ Locally Advanced or [NCT03706365] Genitourinary Cancer Metastatic Breast Cancer CYCLONE 2: A Study of Abiraterone Acetate Plus Prednisone With or Without Abemaciclib [NCT02747004] Breast Cancer (LY2835219) in Participants With Prostate Cancer Next MONARCH 1: A Study of Abemaciclib (LY2835219) Plus Tamoxifen or Abemaciclib Alone in Women With Metastatic Breast Cancer