Background: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. Patients and methods: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for >= 5 years +/- abemaciclib for 2 years. Cohort 1 enrolled patients with >= 4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor >= 5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (>= 20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. Results: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib thorn ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Conclusion: Abemaciclib thorn ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

◥ Purpose: neoMONARCH assessed the biological effects of abe-maciclibincombinationwithanastrozoleintheneoadjuvantsetting. PatientsandMethods: PostmenopausalwomenwithstageI – IIIB HR þ /HER2 (cid:2) breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response. Results: Abemaciclib, alone or in combination with anastrozole, achieved a signi fi cant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and14weeksofcombinationtherapy,46%ofintent-to-treatpatients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea(62%),constipation(44%),andnausea(42%).Abemaciclib,anastrozole,andthecombinationinhibitedcell-cycleprocessesand estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indic-ative of enhanced antigen presentation and activated T-cell pheno-types. Conclusions: Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR þ /HER2 (cid:2) early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.

Background: Abemaciclib is a CDK4 & 6 inhibitor dosed continuously with demonstrated efficacy and an acceptable safety profile in pts with HR+, HER2-negative advanced breast cancer as monotherapy (MONARCH 1) and in combination with endocrine therapy; with fulvestrant (MONARCH 2) or with non-steroidal aromatase inhibitors (MONARCH 3). The most frequent adverse event (AE) is low-grade diarrhea; neutropenia is the most frequent grade 3/4 AE. We describe the timing and management of common AEs in the MONARCH trials. Methods: Enrollment criteria, study designs and key eligibility criteria of MONARCH 1, 2 and 3 have been reported (Dickler et al. 2017; Sledge et al. 2017; Goetz et al. 2017). Pts were advised to initiate antidiarrheal therapy at first sign of diarrhea and notify the investigator, drink fluids. If not improved within 24 hours to < grade 1, treatment was suspended until diarrhea resolved. Dose reductions required for grade ≥3 or persistent grade 2 diarrhea. For grade 3 neutropenia, abemaciclib was held until < grade 2. The dose was reduced for recurrent grade 3 or grade 4 neutropenia. Results: Across MONARCH, the median time to onset of diarrhea was between day 6-8. First dose reductions for diarrhea occurred at a median of 28-41 days. Dose holds for diarrhea were brief, constituting 1.7-3.8% off total treatment time. The median time to onset of grade 3/4 neutropenia was 29-36.5 days, and resolved at a median of 11-15 days. AEs were managed by dose adjustments and/or supportive medication (Table).Table: 339PSummary of Dose Adjustments in Pts Experiencing Diarrhea or NeutropeniaCharacteristicsMONARCH 1 AbemaciclibMONARCH 2 Abemaciclib + FMONARCH 3 Abemaciclib + NSAIN = 132N = 441N = 327Diarrhea (any grade), n(%)119 (90.2)381 (86.4)269 (82.3)Grade 326 (19.7)59 (13.4)31 (9.5)Incidences per patient, n (%)160 (50.4)185 (48.6)124 (46.1)229 (24.4)90 (23.6)52 (19.3)≥330 (25.2)106 (27.8)93 (34.6)Outcome, number (%) of events263995802Not recovered/resolved15 (5.7)106 (10.7)70 (8.7)Treatment change, n (%)119381269Dose reduction of study drug27 (22.7)83 (21.8)45 (16.7)Dose omission32 (24.2)83 (21.8)51 (19.0)Treatment discontinuation1 (0.8)13 (3.4)6 (2.2)Antidiarrheal medication, n (%)80 (60.6)333 (75.5)226 (69.1)Neutropenia (any grade), N (%)49 (37.1)203 (46.0)143 (43.7)Grade ¾32 (24.2)117 (26.5)78 (23.9)Treatment change, n (%)Dose reduction of study drug14 (10.6)44 (10.0)42 (12.8)Dose omission21 (15.9)72 (16.3)57 (17.4)Treatment discontinuation07 (1.6)9 (2.8) Open table in a new tab Conclusions: The dose adjustment strategy used in the MONARCH studies was effective at managing AEs by dose adjustment and/or supportive medication. Understanding the safety profile of abemaciclib can inform AE management and can extend time on treatment. Clinical trial identification: NCT02102490 (MONARCH 1), NCT02107703 (MONARCH 2), NCT02246621 (MONARCH 3). Legal entity responsible for the study: Eli Lilly and Company. Funding: Eli Lilly and Company. Disclosure: H.S. Rugo: Grants/research support: GSK, Genentech/Roche, Novartis, Pfizer, Merck, Eisai, Plexxikon, Macrogenics, Lilly, OBI (all funding to UC Regents only). V. André, S. Barriga, T. Forrester: Employee and stakeholder: Eli Lilly and Company. M.P. Goetz: Consultant: Eli Lilly and Company, bioTheranostics, Novartis, Genomic Health, Eisai, Biovica, and Sermonix; Grant/Research support from Eli Lilly and Pfizer. All other authors have declared no conflicts of interest.

Abstract Background: Based on results from the ATAC and IMPACT trials, Dowsett et al.1 hypothesized that “short-term changes in proliferation in the neoadjuvant setting may be able to predict outcome during adjuvant use of the same treatments.” Recent neoadjuvant studies2,3,4 of novel agents for HR+ breast cancer used Ki67, a biomarker for cell proliferation, as an endpoint for evaluating biological activity. However, the potential of this endpoint for predicting the adjuvant efficacy of therapeutic agents remains highly uncertain, motivating continued study based on clinical data. After curating relevant data from multiple trials (in both the neoadjuvant and adjuvant settings), a statistical model was constructed to evaluate the current evidence regarding this hypothesis. Methods: Data were collated from randomized trials of systemic therapies in post-menopausal women with HR+ breast cancer reporting Ki67 reduction in the neoadjuvant setting (7 studies) or disease-free survival (DFS) in the adjuvant setting (5 studies). A Bayesian hierarchical joint network meta-analysis model was constructed and fit to the data to evaluate: (1) if there is an association between study-level neoadjuvant Ki67 reduction for a given regimen and corresponding adjuvant DFS hazard ratio, and (2) if the relationship does exist, what DFS effect does it predict for various regimens for which only neoadjuvant data are currently available. Results: The results of the statistical model indicate that effect-size based on neoadjuvant Ki67 correlates with adjuvant (DFS) hazard ratio. Using neoadjuvant Ki67 data for several therapies for which adjuvant data are presently unavailable, we demonstrated how forecasts (and associated confidence intervals) of adjuvant effect-size may be produced using the model. Conclusions: While randomized trials yielding paired data from both clinical settings are sparse, this assessment using a statistically rigorous approach sheds additional light on the hypothesis of a correlation between neoadjuvant Ki67 changes and adjuvant DFS improvements. This analysis suggests the potential utility of Ki67 as a surrogate endpoint to screen/prioritize experimental regimens for development in the adjuvant setting. References: 1. Dowsett, M. et al., Clin Cancer Res, 2005. 11(2): p951s-958s. 2. Baselga, J., et al., J of Clin Oncol, 2009. 27(16): p. 2630-2637. 3. Kuter, I., et al., Breast Cancer Res Treat, 2012. 133(1): p. 237-246. 4. Hurvitz, S., et al., Cancer Res, 2017. 77(4 Supplement): p. S4-06-S4-06. Citation Format: Johnston SRD, Frenzel MJ, Thomas ZM, Hu T, Barriga S, Smith IC, Hurvitz S. A multi-study correlative analysis of change in Ki67 in the neoadjuvant setting and disease free survival improvement in the adjuvant setting [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-09-01.

Abstract Background: Abemaciclib is a selective oral inhibitor of CDK4 and CDK6. Dosed on a continuous schedule, abemaciclib showed evidence of antitumor clinical activity in patients (pts) with metastatic BC in monotherapy or in combination with non-steroidal aromatase inhibitor (NSAI) or fulvestrant. NeoMONARCH (NCT02441946) is a Phase 2 trial in women with stage I-IIIB, HR+/HER2- BC evaluating neoadjuvant treatment with abemaciclib + anastrozole, ANZ. As previously reported, NeoMONARCH met its primary endpoint showing abemaciclib, alone or in combination with ANZ, significantly reduced Ki67 expression compared to ANZ alone after 2 weeks (wks) of treatment. Final results are presented here. Methods: 223 pts were randomized (1:1:1) and treated for 2 wks with abemaciclib (150 mg PO Q12H) + ANZ (1 mg PO QD), abemaciclib alone, or ANZ alone. Then, all pts were treated for 14 wks with the combination. Pts were treated with loperamide (2 mg PO Q12H) for 4 wks while receiving abemaciclib. Tumor biopsy was collected at baseline, Wk 2 and Wk 16. Blood samples were collected through Cycle 5 to measure abemaciclib and ANZ concentrations. Primary objective was Ki67 change from baseline to Wk 2. Secondary objectives evaluated after Wk 16 of treatment, were radiologic, pathological and clinical responses, safety, and pharmacokinetics (PK). Exploratory objectives included the mutational analysis of PIK3CA and ESR1 at baseline. Results: Table 1 shows subgroup analyses of percent change in Ki67 from baseline to Wk 2 by disease stage, baseline lymph node (LN) involvement, tumor grade, and tumor size in Ki67 evaluable (KE) population (baseline Ki67 ≥ 5%) comparing combination to ANZ alone. Data for abemaciclib arm will be shown at the meeting. 185 pts completed treatment. At the end of treatment, response rates were radiologic 46.4% (all pts), and caliper 53.6% (all pts), and pCR 3.7% (pts who completed BC surgery assessment). Ki67 end of treatment analysis in 138 pts will be presented. The most common adverse events, all pts, were diarrhea (61.4%; G3: 4.9%), constipation (43.5%; G3: 1.8%), and nausea (41.7%; G3: 2.2%). Treatment discontinuation due to AEs was low (7.6%). Results of PIK3CA and ESR1 mutational analysis, and PK will be presented. Subgroup analyses at Wk 2 of KE population CombinationANZSubgroup treatment comparaison Pts, nGM % ChangePts, nGM % ChangeGMR (95% CI)PKE population59-92.8656-62.780.19 (0.13, 0.28)<0.001Disease Stage I/II51-92.5646-65.840.22 (0.14, 0.34)<0.001III7-95.288-54.910.10 (0.04, 0.27)<0.001Baseline LN Involvement No29-93.1826-62.210.18 (0.11, 0.31)<0.001Yes29-92.7528-69.020.23 (0.13, 0.42)<0.001Tumor Grade 1 or 233-92.8837-69.610.23 (0.15, 0.36)<0.001316-92.7910-59.680.18 (0.05, 0.60)0.011Tumor Size < 2 cm9-93.258-65.460.20 (0.08, 0.35)0.004≥ 2 cm and < 5 cm39-91.2229-62.160.23 (0.14, 0.40)<0.001≥ 5 cm11-94.2419-59.730.14 (0.07, 0.28)<0.001Abbreviations: GM, geometric mean; GMR, geometric mean ratio Conclusions: Abemaciclib + ANZ is an effective treatment with manageable toxicities in pts with HR+/HER2- early BC. Abemaciclib-driven change in Ki67 was not associated with disease stage, baseline LN involvement, tumor grade, or tumor size. Citation Format: Martin M, Hurvitz SA, Chan D, Fernandez-Abad M, Petru E, Rostorfer R, Guarneri V, Huang C-S, Press MF, Costigan TM, Caldwell CW, Wijayawardana S, Turner PK, Barriga S, Slamon DJ. Final results of NeoMONARCH: A phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-01.

Background: MONARCH 2 demonstrated that the addition of abemaciclib, dosed on a continuous schedule at 150 mg twice daily, to fulvestrant (F) significantly improved progression-free survival (PFS) and objective response rate (ORR) compared to placebo (P) plus F (PFS hazard ratio [HR], 0.553, P<.0000001; ORR in measurable disease 48.1% vs 21.3%, P<.001) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) who had progressed on endocrine therapy (ET). Here we present efficacy and safety findings from an exploratory cohort of EN pts from MONARCH 2 not included in the intent-to-treat (ITT) population. Methods: Pts were randomized 2:1 to receive abemaciclib or P + F (500 mg, per label). Pre/perimenopausal women received a gonadotropin-releasing hormone agonist. Pts were not allowed to have had chemotherapy in the advanced setting. Pts were stratified by metastatic site (visceral, bone only, other). The primary endpoint for this analysis was investigator-assessed PFS which was described using the Kaplan-Meier method and a Cox model. Results: Forty-four EN pts were randomized to abemaciclib + F (N = 28) or P + F (N = 16). 46% of pts presented with visceral disease, 77% with measurable disease, and 82% were postmenopausal. At the time of the analysis, 18 pts were still on treatment (13 [46.4%] in the abemaciclib + F arm and 5 [31.3%] in the P + F arm). 18 PFS events were observed (9 [32.1%] in the abemaciclib + F arm and 9 [56.3%] in the P + F arm). The median PFS had not been reached in the abemaciclib + F arm and was 23.1 months in the P + F arm (stratified HR, 0.454; 95% CI: 0.179, 1.154). The ORR in pts with measurable disease was 60.0% (5% complete response [CR]) in the abemaciclib + F arm and 57.1% (0% CR) in the P + F arm. The most common adverse events were diarrhea, nausea, fatigue, and neutropenia. Diarrhea generally occurred in the early cycles and was managed with dose adjustment and conventional anti-diarrheal medication. Conclusions: In this exploratory cohort of EN pts, the addition of abemaciclib to fulvestrant demonstrated a comparable increase in PFS and consistent safety results to those observed in the ITT population in MONARCH 2. Clinical trial identification: NCT02107703 Legal entity responsible for the study: Eli Lilly and Company Funding: Eli Lilly and Company Disclosure: P.A. Kaufman: Consulting/Advisory: Galena Biopharma, Amgen; Research Funding: Eli Lilly and Company. P. Nikolinakos: Advisory board: AstraZeneca. J.T. Beck: My institution receives research grants as part of this study. J.L. Gonzalez-Trujillo: Contract with Lilly, Bristol-Myers Squibb, Roche, Pierre Fabre, Astra for make a corporate-sponsored research. Advisory board for Bristol-Myers Squibb, MSL, Novartis. Speaker for Bristol-Myers Squibb, Novartis. Y. Lin, N. Bourayou: Employment and Stock Ownership: Eli Lilly and Company. S. Barriga: Employment Eli Lilly and Company. D. Headley: Employment and Stock Ownership: Eli Lilly and Company; Stock Ownership: AstraZeneca. A. Llombart Cussac: Honoraria: Roche, Novartis, Pfizer; Consulting/Advisory: Roche, AstraZeneca, Eli Lilly and Company; Research funding: Pfizer, Roche; Travel funds: Roche, Celgene. G.W. Sledge Jr.: Leadership, Stock: Syndax; Honoraria: Symphogen; Consulting/Advisory: Symphogen, Coherus Biosciences, Radius Health, Peregrine Pharmaceuticals, Taiho Pharmaceutical; Research Funding: Roche (Inst); Travel funds: Nektar, Radius Health, Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

Abstract Background: Abemaciclib is a potent oral CDK4 and 6 inhibitor, which demonstrated evidence of clinical activity and an acceptable safety profile on a continuous dosing schedule either as a single agent (MONARCH 1; NCT02102490) or in combination with endocrine therapies in heavily pre-treated women with HR+ metastatic breast cancer (BC).1,2 Methods: neoMONARCH (NCT02441946) is a randomized, multicenter, open-label phase 2 neoadjuvant study comparing the biological effects of abemaciclib plus anastrozole vs abemaciclib monotherapy vs anastrozole monotherapy in women with early-stage HR+, HER2- BC. Patients (pts) were stratified by progesterone receptor status and tumor size and randomized 1:1:1 ([abemaciclib 150mg orally [PO] every 12 hours [Q12H] plus anastrozole 1 mg PO daily [QD]], [abemaciclib 150mg PO Q12H], and [anastrozole 1mg PO QD]). Each regimen was given for 2 weeks; followed by all pts receiving abemaciclib 150mg PO Q12H plus anastrozole 1mg QD for the subsequent 14 weeks. All pts received prophylactic loperamide during the first 28 days of abemaciclib therapy, then at the discretion of the investigator. Eligible pts included postmenopausal women with HR+, HER2- clinical Stage I breast tumor ≥1 cm in diameter, Stage II, Stage IIIA, or IIIB BC. The primary objective: compare biological activity by assessing the percent change from baseline value in Ki67 protein expression after 2 weeks of therapy with the three initial regimens. Clinical activity and safety of the subsequent 14 weeks of therapy of abemaciclib plus anastrozole are evaluated as secondary objectives at surgery. Exploratory objectives included assessment of changes in cell cycle mRNAs by Modaplex (QIAGEN) analyses and PIK3CA and ESR1 mutational analysis in core biopsy samples. Statistical methods: The design provides 80% power to detect superiority of the combination vs anastrozole monotherapy, and 80% power to detect superiority of abemaciclib monotherapy vs anastrozole monotherapy, at a 1-sided alpha level of 0.1. Secondary and exploratory objectives will be presented as descriptive data. Results: Enrollment of 223 pts began August 2015 and was completed August 2016. At a 9 month interim analysis, abemaciclib, given either as monotherapy or in combination with anastrozole showed significantly (p<0.001, n=64) greater suppression of Ki67 after 14 days of dosing than anastrozole alone. The safety profile of the combination differed from that previously reported for abemaciclib 200mg BID monotherapy in the MONARCH 1 study1 and the Phase Ib2 with reduced incidence of diarrhea and hematologic events. Change in proliferation gene mRNAs after 2 weeks of treatment (n=38), in both tumor and blood, appeared to correlate with change in Ki67 expression, with a greater reduction in the abemaciclib-containing arms. Updated data will be presented including safety data for all 223 pts, molecular data on approximately 150 pts who are evaluable for change in Ki67 and mRNA expression at 2 weeks and approximately 100 pts evaluable for clinical efficacy, final Ki67 and RNA expression at surgery. References: 1. Dickler, M.et al., ASCO abstract #510 (2016). 2. Goetz, M.et al., SABCS abstract #P4-13-25 (2015). Citation Format: Hurvitz S, Martin M, Fernández Abad M, Chan D, Rostorfer R, Petru E, Barriga S, Costigan TM, Caldwell CW, Nguyen T, Press M, Slamon D. Biological effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with HR+, HER2- breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S4-06.

Background: Abemaciclib is an oral selective CDK4 & 6 inhibitor dosed on a continuous schedule and has demonstrated efficacy and tolerability as monotherapy and in combination with fulvestrant in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). MONARCH 3 evaluates abemaciclib plus the non-steroidal aromatase inhibitors (NSAI) anastrozole (A) or letrozole (L) as initial therapy in HR+/HER2- ABC. Methods: MONARCH 3 is a double-blind, Phase 3 study of abemaciclib + NSAI (A or L) vs placebo (P) + NSAI in postmenopausal women with HR+/HER2- ABC who have had no prior systemic therapy in the metastatic setting. Endocrine naïve pts or pts with disease relapse >12 months after (neo)adjuvant endocrine therapy (ET) were randomized 2:1 and stratified by metastatic site (visceral, bone only, or other) and prior ET (AI vs no ET vs other). Pts received abemaciclib/P (150 mg, twice daily continuous schedule) + 1 mg A or 2.5 mg L, daily. The primary objective was investigator-assessed progression-free survival (PFS). Secondary objectives included objective response rate (ORR) and safety. The study was powered to 80% at 1-sided α=.025 assuming a hazard ratio (HR) of 0.67 in favor of abemaciclib + NSAI, with analyses at 189 and 240 PFS events. Results: 493 women were randomized to abemaciclib + NSAI (n = 328) or P + NSAI (n = 165). Pt characteristics were: visceral disease (52.9%), measurable disease (80.5%), prior (neo)adjuvant AI (27.4%), and de novo ABC (39.8%). At the interim analysis, 194 PFS events were observed. The PFS was significantly prolonged with a HR of 0.543 (95% CI, 0.409 to 0.723, P=.000021; median PFS: not reached in abemaciclib arm, 14.7 months in placebo arm). In pts with measurable disease, the ORR was 59% in the abemaciclib arm and 44% in the P arm (P=.004). The most frequent adverse events were (abemaciclib vs P arms) diarrhea (81.3% [grade 3: 9.5%, no grade 4] vs 29.8% [grade 3: 1.2%, no grade 4]), neutropenia (41.3% [grade 3/4: 21.1%] vs 1.9% [grade 3/4: 1.2%]), and fatigue (40.1% [grade 3: 1.8%] vs 31.7% [grade 3: 0%]). Conclusions: Abemaciclib + NSAI demonstrated a tolerable safety profile and was an effective initial treatment for pts with HR+/HER2- ABC, significantly improving PFS and ORR. Clinical trial identification: NCT02246621 Legal entity responsible for the study: Eli Lilly and Company Funding: Eli Lilly and Company Disclosure: A. Di Leo: Honoraria, consulting, and travel funds: Daichii-Sankyo, Roche, Novartis, Pfizer, AstraZeneca, Genomic Health, Eisai, Lilly, Pierre Fabre, Bayer, Celgene. Consulting and travel funds: Puma Biotechnology. Research funds: Novartis, Pfizer, AstraZeneca. M. Campone: Honoraria, Consulting/advisory, Speakers' bureau: Novartis, Pfizer, AstraZeneca; Lilly. Travel funds: Novartis, AstraZeneca. J. Sohn: Research Funding: AstraZeneca, Eli Lilly and Company, Novartis, Genentech, Pfizer, MSD Oncology. S. Paluch-Shimon: Consulting/advisory, Speakers' Bureau: Pfizer, Novartis, Roche, AstraZeneca. J. Huober: Honoraria, Consulting/advisory, Travel funds: Novartis, Pfizer, Roche. Honoraria, Consulting: Lilly. O. Tredan: Honoraria, Consulting/Advisory, Travel funds: Lilly, Roche, Novartis, AstraZeneca, Pfizer, Celldex. G.G. Jaliffe: Speakers' Bureau: Roche, Amgen. T. Forrester, M. Frenzel, I.C. Smith, N. Bourayou: Employment and Stock Ownership: Eli Lilly and Company. S. Barriga: Employment: Eli Lilly and Company. M.P. Goetz: Consulting/Advisory: Eli Lilly and Company, Biotheranostics. Research funding: Eli Lilly and Company. All other authors have declared no conflicts of interest.

Background: Abemaciclib is an oral, selective inhibitor of CDK4 & 6 that has demonstrated activity in different tumor types. In a phase 1 trial, treatment emergent adverse events (TEAEs) of increased creatinine, grade 1 or 2 severity by Common Terminology Criteria for Adverse Events (CTCAE v4.0) were reported in > 10% of patients (pts) who received abemaciclib monotherapy1. In vitro, abemaciclib and its major metabolites inhibit renal transporters OCT2, MATE1, and MATE2-K2. Methods: MONARCH 1 is a phase 2 single-arm study designed to evaluate safety and efficacy of abemaciclib monotherapy in women with HR+/HER2- MBC whose disease progressed on/after endocrine- and chemotherapy. Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity occurred. We retrospectively analyzed changes in serum creatinine, blood urea nitrogen (BUN), cystatin C, and calculated glomerular filtration rate (GFR) based on cystatin C using central lab values. TEAEs (CTCAE v4.0), dose delays, and treatment discontinuation associated with renal events were examined. Results: Of the 132 pts treated, 130 pts had central laboratory data available, and 128 pts (98.5%) experienced an increased serum creatinine: 61 pts (46.9%) grade 1, 66 pts (50.8%) grade 2, 1 pt (0.8%) grade 3. Creatinine increases occurred during cycle 1 and remained elevated but stable during treatment. Serum creatinine decreased following treatment discontinuation. No changes in mean BUN, cystatin C or estimated GFR were observed. TEAEs of increased serum creatinine were reported in 17 pts (12.9%); one was grade 3. Due to increased serum creatinine, 2 pts experienced dose reductions, 2 pts dose omissions, and 1 pt treatment discontinuation. Serious AEs (SAEs) of increased creatinine was were experienced by 4 patients; 3 were possibly related to abemaciclib. A non-drug related SAE of acute kidney injury was reported for 1 pt. Review of all reported AEs/SAEs failed to indicate any evidence of renal impairment. The Standardized MedDRA Queries (SMQ) acute renal failure was used to search and identify all reported cases of increased creatinine with or without acute kidney injury. Twenty pts (15.2%) who experienced an AE were included in this category: 4 pts (3.0%) met the narrow term SMQ, and 17 pts (12.9%) the broad term SMQ. Conclusions: Safety data from the MONARCH 1 study shows a causal association of the reversible increased blood creatinine with abemaciclib therapy, but not as a result of renal injury, renal insufficiency, or impaired renal function. The rise in serum creatinine is consistent with in vitro data indicating that abemaciclib is a competitive inhibitor of renal efflux transporters of creatinine2. References: 1. Patnaik, Amita, et al. 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. Cancer Discovery (2016). 2. Kulanthaivel, P. et al. Pharmacokinetic Drug Interactions Between Abemaciclib and CYP3A Inducers and Inhibitors. American Association for Cancer Research - 107th Annual Meeting, abstract #CT153 (2016). Citation Format: Tolaney S, Lam AQ, Mukundan S, Nanda S, Cox J, Barriga S. Analysis of renal function in MONARCH 1: A phase 2 study of abemaciclib, a CDK4 & 6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-15-01.

Background: Abemaciclib is an oral, selective inhibitor of CDK4 u0026 6 that has demonstrated activity in different tumor types. In a phase 1 trial, treatment emergent adverse events (TEAEs) of increased creatinine, grade 1 or 2 severity by Common Terminology Criteria for Adverse Events (CTCAE v4.0) were reported in u003e 10% of patients (pts) who received abemaciclib monotherapy 1 . In vitro, abemaciclib and its major metabolites inhibit renal transporters OCT2, MATE1, and MATE2-K 2 . Methods: MONARCH 1 is a phase 2 single-arm study designed to evaluate safety and efficacy of abemaciclib monotherapy in women with HR+/HER2- MBC whose disease progressed on/after endocrine- and chemotherapy. Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity occurred. We retrospectively analyzed changes in serum creatinine, blood urea nitrogen (BUN), cystatin C, and calculated glomerular filtration rate (GFR) based on cystatin C using central lab values. TEAEs (CTCAE v4.0), dose delays, and treatment discontinuation associated with renal events were examined. Results: Of the 132 pts treated, 130 pts had central laboratory data available, and 128 pts (98.5%) experienced an increased serum creatinine: 61 pts (46.9%) grade 1, 66 pts (50.8%) grade 2, 1 pt (0.8%) grade 3. Creatinine increases occurred during cycle 1 and remained elevated but stable during treatment. Serum creatinine decreased following treatment discontinuation. No changes in mean BUN, cystatin C or estimated GFR were observed. TEAEs of increased serum creatinine were reported in 17 pts (12.9%); one was grade 3. Due to increased serum creatinine, 2 pts experienced dose reductions, 2 pts dose omissions, and 1 pt treatment discontinuation. Serious AEs (SAEs) of increased creatinine was were experienced by 4 patients; 3 were possibly related to abemaciclib. A non-drug related SAE of acute kidney injury was reported for 1 pt. Review of all reported AEs/SAEs failed to indicate any evidence of renal impairment. The Standardized MedDRA Queries (SMQ) acute renal failure was used to search and identify all reported cases of increased creatinine with or without acute kidney injury. Twenty pts (15.2%) who experienced an AE were included in this category: 4 pts (3.0%) met the narrow term SMQ, and 17 pts (12.9%) the broad term SMQ. Conclusions: Safety data from the MONARCH 1 study shows a causal association of the reversible increased blood creatinine with abemaciclib therapy, but not as a result of renal injury, renal insufficiency, or impaired renal function. The rise in serum creatinine is consistent with in vitro data indicating that abemaciclib is a competitive inhibitor of renal efflux transporters of creatinine 2 . References : 1. Patnaik, Amita, et al. 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. Cancer Discovery (2016). 2. Kulanthaivel, P. et al. Pharmacokinetic Drug Interactions Between Abemaciclib and CYP3A Inducers and Inhibitors. American Association for Cancer Research - 107th Annual Meeting, abstract #CT153 (2016). Citation Format: Tolaney S, Lam AQ, Mukundan S, Nanda S, Cox J, Barriga S. Analysis of renal function in MONARCH 1: A phase 2 study of abemaciclib, a CDK4 u0026 6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-15-01.

Background: Abemaciclib is a potent oral CDK4- and 6-inhibitor. NeoMONARCH (NCT02441946) was a randomized, multicenter, open-label phase 2 neoadjuvant study in postmenopausal women with early-stage HR+/HER2- breast cancer (BC). Materials (patients) and methods: 224 patients stratified by progesterone receptor status and tumor size were randomized 1:1:1 to receive abemaciclib (150mg Q12h) plus anastrozole (1mg QD), abemaciclib monotherapy, or anastrozole monotherapy for 2 weeks, then all patients received abemaciclib plus anastrozole for 14 weeks. Abemaciclib-treated patients received prophylactic loperamide during the first 28 days of therapy, then at the discretion of the investigator. The primary objective was to assess the change from baseline Ki-67 expression after 2 weeks of therapy with abemaciclib plus anastrozole vs abemaciclib monotherapy and anastrozole monotherapy. Clinical activity and safety were evaluated as secondary objectives. The statistical design provided 80% power to detect superiority of the combination vs anastrozole, at a 1-sided alpha level of 0.1. Results: 161/223 treated patients were evaluable for the primary endpoint. Abemaciclib plus anastrozole (n = 56) as well as in monotherapy (n = 51) significantly reduced Ki-67 expression vs anastrozole monotherapy (n = 54) at week 2 based on geometric mean change and complete cell cycle arrest (Ki-67<2.7%). Change in proliferation gene mRNAs at 2 weeks (Modaplex) correlated with the change in Ki-67 expression. Objective response rate was 54.7% (n = 106) for patients who completed the treatment with abemaciclib and anastrozole. Most common adverse events were diarrhea, constipation, nausea and fatigue. Conclusion: Monotherapy with abemaciclib as well as abemaciclib plus anastrazole showed significantly higher biological activity compared with anastrozole alone and the study's primary endpoint was met. The majority of patients experienced an objective response. No new safety signals for abemaciclib when combined with anastrozole were detected. These data support continued evaluation of abemaciclib in early-stage BC.

Background: Abemaciclib is a potent oral CDK4 and 6 inhibitor, which demonstrated evidence of clinical activity and an acceptable safety profile on a continuous dosing schedule either as a single agent (MONARCH 1; NCT02102490) or in combination with endocrine therapies in heavily pre-treated women with HR+ metastatic breast cancer (BC). 1,2 Methods: neoMONARCH (NCT02441946) is a randomized, multicenter, open-label phase 2 neoadjuvant study comparing the biological effects of abemaciclib plus anastrozole vs abemaciclib monotherapy vs anastrozole monotherapy in women with early-stage HR+, HER2- BC. Patients (pts) were stratified by progesterone receptor status and tumor size and randomized 1:1:1 ([abemaciclib 150mg orally [PO] every 12 hours [Q12H] plus anastrozole 1 mg PO daily [QD]], [abemaciclib 150mg PO Q12H], and [anastrozole 1mg PO QD]). Each regimen was given for 2 weeks; followed by all pts receiving abemaciclib 150mg PO Q12H plus anastrozole 1mg QD for the subsequent 14 weeks. All pts received prophylactic loperamide during the first 28 days of abemaciclib therapy, then at the discretion of the investigator. Eligible pts included postmenopausal women with HR+, HER2- clinical Stage I breast tumor ≥1 cm in diameter, Stage II, Stage IIIA, or IIIB BC. The primary objective: compare biological activity by assessing the percent change from baseline value in Ki67 protein expression after 2 weeks of therapy with the three initial regimens. Clinical activity and safety of the subsequent 14 weeks of therapy of abemaciclib plus anastrozole are evaluated as secondary objectives at surgery. Exploratory objectives included assessment of changes in cell cycle mRNAs by Modaplex (QIAGEN) analyses and PIK3CA and ESR1 mutational analysis in core biopsy samples. Statistical methods: The design provides 80% power to detect superiority of the combination vs anastrozole monotherapy, and 80% power to detect superiority of abemaciclib monotherapy vs anastrozole monotherapy, at a 1-sided alpha level of 0.1. Secondary and exploratory objectives will be presented as descriptive data. Results: Enrollment of 223 pts began August 2015 and was completed August 2016. At a 9 month interim analysis, abemaciclib, given either as monotherapy or in combination with anastrozole showed significantly (p 1 and the Phase Ib 2 with reduced incidence of diarrhea and hematologic events. Change in proliferation gene mRNAs after 2 weeks of treatment (n=38), in both tumor and blood, appeared to correlate with change in Ki67 expression, with a greater reduction in the abemaciclib-containing arms. Updated data will be presented including safety data for all 223 pts, molecular data on approximately 150 pts who are evaluable for change in Ki67 and mRNA expression at 2 weeks and approximately 100 pts evaluable for clinical efficacy, final Ki67 and RNA expression at surgery. References: 1. Dickler, M.et al., ASCO abstract #510 (2016). 2. Goetz, M.et al., SABCS abstract #P4-13-25 (2015). Citation Format: Hurvitz S, Martin M, Fernandez Abad M, Chan D, Rostorfer R, Petru E, Barriga S, Costigan TM, Caldwell CW, Nguyen T, Press M, Slamon D. Biological effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with HR+, HER2- breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S4-06.

Abemaciclib is a potent, oral small-molecule inhibitor of CDK4 and 6 administered on a continuous dosing schedule, with evidence of single-agent antitumor activity and an acceptable safety profile when combined with an aromatase inhibitor in patients (pts) with refractory HR+ metastatic BC. This phase II study (NCT02441946) compared the biologic activity of neoadjuvant abemaciclib plus anastrozole (ANZ; combo), abemaciclib monotherapy, and ANZ monotherapy in women with untreated early-stage invasive BC. All pts were randomized (1:1:1) for the first 2 weeks and then received combo therapy during the subsequent 14 weeks. Abemaciclib was administered 150 mg orally (PO) every 12 hours, and ANZ was administered 1 mg PO daily. Loperamide was administered as primary prophylaxis with each abemaciclib dose. The primary objective was the change in tissue Ki67 from baseline to week 2. Additional objectives included safety; clinical, radiologic, and pathological response; and changes in proliferation-associated genes (PAGs). At the pre-specified 9-month interim analysis, data were available for safety (173 pts), Ki67 (64 pts), and PAGs (51 pts). Reduction in Ki67 geometric mean percent change from baseline was significantly greater (one-sided P < 0.001) with combo (-93.5%; n = 23) and abemaciclib (-93.1%; n = 19) than ANZ therapy (-71.0%; n = 22). There were a greater number of Ki67 responders (pts with Ki67 <2.7% at week 2) in combo and abemaciclib therapies than ANZ alone (69.6%, 68.4%, and 22.7%, respectively). Results from exploratory analyses of PAGs will be shown.Tabled 1Select adverse events through cycle 1 (first 2 weeks) and all cycles*Combo (n = 56)Abemaciclib monotherapy (n = 58)ANZ monotherapy (n = 59)Total (N = 173)Cycle 1Cycle 1Cycle 1Cycle 1All CyclesDiarrheaAny grade14 (25.0)15 (25.9)029 (16.8)73 (42.2)Grade 32 (3.6)002 (1.2)5 (2.9)ConstipationAny grade10 (17.9)†11 (19.0)†2 (3.4)23 (13.3)40 (23.1)Grade 31 (1.8)001 (0.6)1 (0.6)Post baseline laboratory assessments beginning at Cycle 2††Abemaciclib + ANZ (N = 162)Creatinine increasedAny grade----151 (93.2)Grade 3----1 (0.6)NeutropeniaAny grade----105 (64.8)Grade 3----10 (6.2)Grade 4----2 (1.2)*All pts switched to combination therapy after cycle 1.†1 pt had unknown grade constipation.††Pts with >1 post baseline assessment. Open table in a new tab *All pts switched to combination therapy after cycle 1. †1 pt had unknown grade constipation. ††Pts with >1 post baseline assessment. Abemaciclib therapies reduced Ki67 more than ANZ alone. No new safety concerns were identified and diarrhea was less frequent and severe due to loperamide prophylaxis.