Martin Frenzel

MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy.

Purpose MONARCH 2 ( ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC). Patients and Methods MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety. Results Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%). Conclusions Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET.

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.

UNLABELLED 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 experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53. ©2016 AACR.See related commentary by Lim et al., p. 697This article is highlighted in the In This Issue feature, p. 681.

MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2− Metastatic Breast Cancer

Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor–positive (HR+), HER2− metastatic breast cancer (MBC). Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2− MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS). Results: Patients (n = 132) had a median of 3 (range, 1–8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3–27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%). Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2− metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity. Clin Cancer Res; 23(17); 5218–24. ©2017 AACR.

Abstract CT232: Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer

LY2835219 is a novel cell cycle inhibitor selective for the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6), which act in a protein complex with D-type cyclins to enable G1 to S cell cycle progression. Preclinical models indicate this complex plays a critical role in breast cancer. We conducted a phase I study with expansion cohorts to evaluate the safety, pharmacokinetics, and antitumor activity of LY2835219 in 5 different tumor types: glioblastoma; melanoma; and cancers of the lung, colon/rectum and breast. In the expansion cohorts, LY2835219 was administered continuously at 150-200mg orally every 12 hours on Days 1-28 of a 28-day cycle. RECIST v1.1 was used to assess tumor response. The most common possibly related treatment-emergent adverse events across the expansion cohorts (n=132) included diarrhea (5% G3/4), nausea (3% G3/4), fatigue (2% G3/4), vomiting (2% G3/4) and neutropenia (11% G3/4). In the metastatic breast cancer (MBC) cohort, 47 patients with a median of 7 prior systemic regimens received therapy with LY2835219. Across all MBC patients, 9 achieved a best overall response of confirmed partial response (PR), 24 achieved stable disease (SD), 11 had progressive disease (PD), and 3 were not evaluable for response. Among the 36 HR+ patients, there were 9 confirmed partial responses for an ORR of 25%. In addition, 20 of these 36 HR+ patients (56%) had SD: 7 patients had SD Citation Format: Amita Patnaik, Lee S. Rosen, Sara M. Tolaney, Anthony W. Tolcher, Jonathan W. Goldman, Leena Gandhi, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew W. Rasco, Scott P. Myrand, Palaniappan Kulanthaivel, Lily Li, Martin Frenzel, Damien M. Cronier, Edward M. Chan, Keith T. Flaherty, Patrick Y. Wen, Geoffrey I. Shapiro. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT232. doi:10.1158/1538-7445.AM2014-CT232

Abstract P5-19-13: Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer

Background: Abemaciclib, a small molecule inhibitor with selectivity against cyclin-dependent kinases 4 and 6 (CDK4/6), induces G1 arrest in Rb-proficient human breast cancers. In an early phase clinical trial, the safety and antitumor activity of abemaciclib (LY2835219) were evaluated in 2 cohorts of patients with metastatic breast cancer (mBC). One cohort evaluated single-agent abemaciclib in an unselected population of patients with mBC [Part D], while the combination of abemaciclib plus fulvestrant was evaluated in patients with hormone receptor positive (HR+) mBC [Part G]. We previously reported early results for these 2 cohorts of patients with mBC treated with either single-agent abemaciclib or the combination of abemaciclib plus fulvestrant (Patnaik et al, ASCO 2014). In the single-agent cohort, 47 patients with previously treated mBC were enrolled (36 HR+). All patients with >30% tumor reduction had HR+ mBC (13 of 36 patients). In this group of 13 patients with HR+ mBC, 9 patients had confirmed response for an objective response rate of 25%, and 4 patients had unconfirmed response. This study was ongoing with 14 of 36 HR+ mBC patients on treatment at time of analysis (range 238-471 days). Patients continuing on single-agent abemaciclib included 4 patients with unconfirmed response and 6 patients with confirmed response. For the combination of abemaciclib plus fulvestrant, 18 patients with HR+ mBC enrolled and 13 patients (72%) were still on treatment (range 31-143 days) at the time of analysis. Methods: In the single-agent cohort, patients with mBC were treated with abemaciclib at 150 or 200mg orally every 12 hours on a continuous schedule. In the combination cohort, patients with HR+ mBC (n=18) were treated with the combination of abemaciclib plus fulvestrant. Patients received abemaciclib at 200mg orally every 12 hours on a continuous schedule. Patients also received fulvestrant at 500mg intramuscularly every month. NCI CTCAE v4.0 was used to grade adverse events (AEs) and RECIST v1.1 was used to assess tumor response. Results: In the single-agent cohort, patients began enrolling in May 2012 with the last patient enrolled in March 2013. Patients had a median of 7 prior systemic therapies and 81% of patients had ≥2 metastatic sites. In the combination cohort, patients began enrolling in September 2013 with the last patient enrolled in January 2014. Patients in the combination cohort had a median of 4 prior systemic therapies and 67% of patients had ≥2 metastatic sites. An updated analysis will be presented for objective response rate, duration of treatment and clinical benefit rate and will include an additional 6 months of information for both the single-agent and combination cohorts. New analyses will include time to response, duration of response, change in tumor size over time, and characteristics of responders. In addition, safety data will include longer term follow-up through approximately September 2014. Conclusions: Abemaciclib is an oral cell cycle inhibitor that demonstrates single-agent activity against mBC, especially for HR+ disease. Based on its safety and efficacy profile, abemaciclib warrants further clinical investigation in confirmatory studies, both as a single agent and in combination with endocrine therapy. Citation Format: Sara M Tolaney, Lee S Rosen, Muralidhar Beeram, Jonathan W Goldman, Leena Gandhi, Anthony W Tolcher, Kyriakos P Papadopoulos, Drew W Rasco, Scott P Myrand, Palaniappan Kulanthaivel, Joan M Andrews, Martin Frenzel, Damien M Cronier, Edward M Chan, Keith T Flaherty, Patrick Y Wen, Geoffrey I Shapiro, Amita Patnaik. Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-13.

Abstract CT092: A phase II study of neoadjuvant abemaciclib (LY2835219) in postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (neoMONARCH)

Purpose: Abemaciclib (LY2835219) is a potent, selective small molecule inhibitor of cyclin dependent kinase (CDK)4 and CDK6, which has been shown to inhibit cell cycle progression by preventing the phosphorylation and functional inactivation of the Rb tumor-suppressor protein. Cell cycle dysfunction due to abnormalities in the CDK4 and CDK6 pathway occurs in breast cancer. Abemaciclib demonstrated single-agent activity in heavily pretreated women with HR+ metastatic breast cancer (Study I3Y-MC-JPBA), and has an acceptable safety profile as a single agent and when combined with aromatase inhibitors. neoMONARCH (NCT02441946) is a randomized, open-label phase II study comparing the biologic activity of abemaciclib plus anastrozole, abemaciclib monotherapy, and anastrozole monotherapy in postmenopausal women with early-stage HR+, HER2- breast cancer by assessing percentage change from baseline in Ki67 expression after 2 weeks of therapy. Secondary objectives are to evaluate response rates, safety, quality of life, and pharmacokinetics of abemaciclib and anastrozole with up to 22 additional weeks of neoadjuvant therapy. Methods: Approximately 220 patients with HR+, HER2- breast cancer who have received no prior treatment for newly diagnosed invasive breast cancer will be randomized 1:1:1 (Arm A [abemaciclib 150 mg orally q12hrs plus anastrozole 1 mg orally q24hrs], Arm B [abemaciclib 150 mg orally q12hrs], Arm C [anastrozole 1 mg orally q24hrs]) for 2 weeks, with stratification based on progesterone receptor status and tumor size ( Statistical methods: The study has >80% power to detect a superior effect of the combination therapy or of abemaciclib alone over anastrozole alone in reducing Ki67 expression at a 1-sided alpha level of 0.1, assuming a geometric mean change in Ki67 expression of -82% for anastrozole alone and -91% for combination therapy or abemaciclib alone. Present accrual: 73 patients. Citation Format: Sara A. Hurvitz, Jeanne Marie Schilder, Martin Frenzel, Miguel Martin. A phase II study of neoadjuvant abemaciclib (LY2835219) in postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (neoMONARCH). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT092.

Abstract OT1-1-07: A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2)

Background: Abemaciclib (LY2835219), an oral drug administered twice daily on a continuous schedule, is a cell cycle inhibitor of both CDK4 and CDK6. In Study I3Y-MC-JPBA, abemaciclib demonstrated evidence of single agent activity in a tumor-specific cohort of patients with metastatic breast cancer (MBC) and a median of 7 prior therapies; all responses observed were in women with HR+ disease. Abemaciclib also demonstrated an acceptable safety profile both as a single agent and in combination with fulvestrant. Based on these results, abemaciclib has been entered into a Phase III study (MONARCH 2) in combination with fulvestrant for women with locally advanced or metastatic hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Trial design: MONARCH 2 (NCT02107703) is a randomized, double-blind, placebo-controlled Phase III study of fulvestrant with or without abemaciclib for women with HR+, HER2- locally advanced (not amenable to curative treatment by surgery) or metastatic breast cancer. Patients will be randomized 2:1 (Arm A [abemaciclib plus fulvestrant]: Arm B [placebo plus fulvestrant] with stratification based on the nature of disease (visceral metastases versus bone only metastases versus other) and sensitivity to endocrine therapy (no prior endocrine therapy versus primary resistance versus secondary resistance). Abemaciclib (200 mg every 12 hours [Q12H] on Days 1 to 28 of a 28-day cycle) or placebo will be given orally and fulvestrant 500 mg will be administered intramuscularly on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and subsequent cycles. Eligibility criteria: Postmenopausal women with HR+, HER2- inoperable locally advanced or metastatic breast cancer who have either relapsed after prior endocrine therapy or have not received prior endocrine therapy are eligible. Patients are required to have either measurable disease or non-measurable bone only disease, adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤1. Specific aims: The primary objective of MONARCH 2 is to compare PFS between two treatment arms: abemaciclib plus fulvestrant versus placebo plus fulvestrant for women with HR+, HER2- locally advanced or metastatic breast cancer. Secondary objectives are to compare overall survival, objective response rate, clinical benefit rate, safety, pharmacokinetics and quality of life. Statistical methods: The study has 90% power to detect an increase in PFS of approximately 42% (hazard ratio = .703). Assuming a median PFS of 6.5 mos. in the control arm, this corresponds to a 2.75 month increase in the median PFS to 9.25 mos. PFS and OS will be hierarchically tested to maintain an overall type I error rate of 2.5%. Present accrual and target accrual: Target accrual is approximately 550 patients. Contact information: For further information please contact 1-877-CTLILLY (1-877-285-4559). Citation Format: Antonio Llombart, Masakazu Toi, Suzanne R Klise, Martin Frenzel, Edward M Chan, George W Sledge. A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-07.