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Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

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Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors Published OnlineFirst May 23, 2016; DOI: 10.1158/2159-8290.CD-16-0095 RESEARCH ARTICLE Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors Amita Patnaik1, Lee S. Rosen2, Sara M. Tolaney3, Anthony W. Tolcher1, Jonathan W. Goldman2, Leena Gandhi3, Kyriakos P. Papadopoulos1, Muralidhar Beeram1, Drew W. Rasco1, John F. Hilton3, Aejaz Nasir4, Richard P. Beckmann4, Andrew E. Schade4, Angie D. Fulford4, Tuan S. Nguyen4, Ricardo Martinez4, Palaniappan Kulanthaivel4, Lily Q. Li4, Martin Frenzel4, Damien M. Cronier4, Edward M. Chan4, Keith T. Flaherty5, Patrick Y. Wen3, and Geoffrey I. Shapiro3 ABSTRACT We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor- specific cohorts for breast cancer, non–small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor–positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months. SIGNIFICANCE: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experi- ence demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 1–14. ©2016 AACR. 1South Texas Accelerated Research Therapeutics, San Antonio, Texas. Corresponding Authors: Amita Patnaik, South Texas Accelerated Research 2University of California, Los Angeles, California. 3Dana-Farber Cancer Therapeutics, 4383 Medical Drive, San Antonio, TX 78229. Phone: 210- Institute, Boston, Massachusetts. 4Eli Lilly and Company, Indianapolis, 593-5250; Fax: 210-615-1121; E-mail: [email protected]; and Indiana. 5Massachusetts General Hospital, Boston, Massachusetts. Geoffrey Shapiro, Early Drug Development Center, Department of Medical Note: Supplementary data for this article are available at Cancer Discovery Oncology, Dana-Farber Cancer Institute, Mayer 446, 450 Brookline Avenue, Online (http://cancerdiscovery.aacrjournals.org/). Boston, MA 02215. Phone: 617-632-4942; Fax: 617-632-1977; E-mail: [email protected] Presented in part at meetings of the American Society of Clinical Oncology 2013 and 2014, the American Association for Cancer Research 2014, and doi: 10.1158/2159-8290.CD-16-0095 the San Antonio Breast Cancer Symposium 2014. ©2016 American Association for Cancer Research. Current address for J.F. Hilton: University of Ottawa, Ottawa, Ontario, Canada. OF1 | CANCER DISCOVERY JULY 2016 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst May 23, 2016; DOI: 10.1158/2159-8290.CD-16-0095 INTRODUCTION CDK6 (21). Consistent with its activity against CDK4 and CDK6, abemaciclib inhibits RB phosphorylation and leads Cyclin-dependent kinases (CDK) 4 and 6 interact with to G1 arrest in RB-proficient cell lines (21). In a colorectal D-type cyclins to phosphorylate the retinoblastoma (RB) cancer xenograft model used to develop an integrated phar- tumor suppressor protein and promote G1 to S phase cell- macokinetic/pharmacodynamic model, abemaciclib can be cycle progression (1). The activity of these kinases is regu- dosed orally on a continuous schedule to achieve sustained lated by the phosphorylation, ubiquitination, and binding of target inhibition and demonstrates not only durable cell- endogenous cellular inhibitors from the INK4 family (2–5). cycle inhibition but also single-agent antitumor activity The INK4–CDK4/CDK6–cyclin D axis is often disrupted in (21, 22). Tumor growth inhibition is observed in multiple cancer by both genetic and epigenetic mechanisms, result- other human cancer xenograft models, including those ing in increased kinase activity (6–8). In addition, exces- derived from non–small cell lung cancer (NSCLC), mela- sive CDK4 or CDK6 activity may suppress senescence and noma, glioblastoma, and mantle cell lymphoma (21–23). directly contribute to both initiation and maintenance of Abemaciclib distributes across the blood–brain barrier and the transformed state (9–15). Ectopic expression of INK4- prolongs survival in an intracranial glioblastoma xeno- inhibitory proteins in cancer cells reverses these tumorigenic graft model (24), suggesting potential efficacy against pri- effects, indicating the potential of CDK4 and CDK6 as mary and metastatic tumors involving the central nervous antineoplastic drug targets (16). Furthermore, mouse mod- system. els lacking D-type cyclins or CDK4 or CDK6 demonstrate Based on preclinical investigations, we conducted a multi- context-specific roles for these proteins in proliferation that center study including phase I dose escalation and tumor- is restricted by cell type, suggesting a therapeutic window specific cohorts. The primary objective was to evaluate for inhibition of CDK4 and CDK6 as an anticancer strategy safety and tolerability of abemaciclib when administered (17–20). orally on a continuous schedule to patients with advanced Abemaciclib (LY2835219) is a small-molecule inhibitor cancer. Secondary objectives were to determine pharmacoki- of CDK4 and CDK6 that is structurally distinct from other netics, evaluate biomarkers, document antitumor activity, dual inhibitors (such as palbociclib and ribociclib) and and establish a recommended dose range for patients with notably exhibits greater selectivity for CDK4 compared with cancer. JULY 2016 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst May 23, 2016; DOI: 10.1158/2159-8290.CD-16-0095 RESEARCH ARTICLE Patnaik et al. RESULTS Safety Enrollment In the single-agent tumor-specific cohorts n( = 173), the most common (>10%) treatment-emergent adverse events A total of 225 patients with advanced cancer were enrolled (TEAE) possibly related to abemaciclib involved fatigue and between December 28, 2009, and April 28, 2014. Thirty-three the gastrointestinal (diarrhea, nausea, vomiting, anorexia, patients were enrolled in dose escalation (Supplementary and weight loss), renal (increased creatinine), or hemato- Table S1) and 192 patients in tumor-specific cohorts for poietic (leukopenia, neutropenia, thrombocytopenia, and breast cancer (n = 47, single-agent therapy with abemaciclib), anemia) systems (Table 1). These events occurred early, NSCLC (n = 68), glioblastoma (n = 17), melanoma (n = 26), within 1 to 2 weeks of initiating treatment, and were revers- colorectal cancer (n = 15), and hormone receptor (HR)–positive ible. There were no study-related deaths and only 2 grade 4 breast cancer (n = 19, combination therapy with abemaciclib events (both neutropenia). Among the 173 patients, febrile + fulvestrant). Baseline patient and disease characteristics neutropenia was observed in 1 patient with breast cancer are summarized by cohort and in aggregate for the tumor- who received abemaciclib at a dose of 150 mg Q12H. In the specific cohorts in Supplementary Table S2. Notably, most tumor-specific cohorts, grade 3 events involving the gastro- patients had ≥2 metastatic sites and had received multiple intestinal and hematopoietic systems occurred in ≤5% and prior systemic therapies for advanced cancer. ≤10% of patients, respectively; grade 3 events involving the renal system were not observed, with grade 1 and 2 events Dose Escalation occurring in 7% and 4% of patients, respectively. Due to the During dose escalation, both once-daily (n = 13) and twice- incidence of grade 1 and 2 diarrhea at 200 mg Q12H, the daily (n = 20) schedules were investigated. On the once-daily alternate starting dose of 150 mg Q12H was also explored. (Q24H) schedule, sequential cohorts of patients received abe- Among the 173 patients, dose reductions were required for maciclib at dose levels of 50 mg (n = 4), 100 mg (n = 3), 150 mg 17 of 81 patients (21%) receiving a dose of 150 mg Q12H (n = 3), or 225 mg (n = 3). Dose-limiting toxicity (DLT) was not and 40 of 92 patients (43%) receiving a dose of 200 mg observed, and the maximum tolerated dose (MTD) was not Q12H. reached. On the twice-daily (Q12H) schedule, sequential cohorts For patients with HR-positive breast cancer receiving com- of patients received abemaciclib at dose levels of 75 mg (n = 3), bination therapy with abemaciclib plus fulvestrant (n = 19), 100 mg (n = 4), 150 mg (n = 3), 200 mg (n = 7), and 275 mg (n = 3). the most common possibly related TEAEs were similar to Febrile neutropenia was not observed on either schedule. At those observed in the single-agent cohorts (Supplementary 200 mg Q12H,
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