Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2- Breast Cancer

Abstract

Purpose: neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting.

Patients and methods: Postmenopausal women with stage I-IIIB HR+/HER2- 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 significant 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 and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes.

Conclusions: Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR+/HER2- early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.

Trial registration: ClinicalTrials.gov NCT02441946.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

S.A. Hurvitz reports receiving commercial research grants from Ambrx, Amgen, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Genentech/Roche, GlaxoSmithKline, Immunomedics, Lilly, Novartis, Pfizer, Macrogenics, OBI Pharma, Pieris, PUMA, Sanofi, Seattle Genetics, Medivation, and Merrimack, and is an advisory board member/unpaid consultant for GlaxoSmithKline, Novartis, AstraZeneca, Lilly, Amgen, and Daiichi Sankyo. M. Martin is a paid consultant for Roche, Novartis, PUMA, AstraZeneca, Amgen, Taiho Oncology, Pharmamar, Eli Lilly, and Daiichi Sankyo, and reports receiving commercial research grants from Roche, Novartis, and PUMA. M.F. Press is a paid consultant for Biocartis, Puma Biotechnology, Cepheid, Karyopharm Therapeutics, Science Branding Communications, Novartis, and Zymeworks, Inc., and reports receiving commercial research grants from Cepheid, Eli Lilly, F. Hoffmann-La Roche AG, and Novartis, and other remuneration from Amgen, Inc. M. Fernandez-Abad is an advisory board member/unpaid consultant for Eli Lilly. E. Petru is an advisory board member/unpaid consultant for Abemaciclib. V. Guarneri reports receiving speakers bureau honoraria from and is an advisory board member/unpaid consultant for Eli Lilly. C. Huang reports receiving commercial research grants from Eli Lilly; other commercial research support from Roche, Novartis, MSD, EirGenix, OBI Pharma, Daiichi Sankyo, AstraZeneca, and Pfizer; and speakers bureau honoraria from Amgen, Pfizer, Roche, and Novartis, and is an advisory board member/unpaid consultant for Eli Lilly, Pfizer, Roche, and Amgen. S. Barriga, P.J. Ebert, A. Aggarwal, and V.M. Jansen are employees/paid consultants for and hold ownership interest (including patents) in Eli Lilly. S.R. Wijayawardana, A. Hossain, and J. Liu are employees/paid consultants for Eli Lilly. D.J. Slamon is a paid consultant for Eli Lilly, Novartis, and Pfizer; reports receiving commercial research grants from Novartis; and holds ownership interest (including patents) in Pfizer, Amgen, Seattle Genetics, and BioMarin. No potential conflicts of interest were disclosed by the other authors.

©2019 American Association for Cancer Research.

Figures

Figure 1.

Antiproliferative effects of abemaciclib, anastrozole (ANZ), and combination therapy on HR+/HER2− breast cancer. A, Individual paired Ki67 expression at baseline and 2 weeks after treatment with abemaciclib + ANZ, abemaciclib, and anastrozole. B, Geometric mean percentage suppression of Ki67 from baseline to 2 weeks by treatment arms. P values are based on a one-sided hypothesis test from a linear model with treatment, progesterone receptor status (positive vs. negative/unknown), and tumor size (<2 cm vs. ≥2 cm and <5 cm vs. ≥5 cm) as fixed effects. C, Mean percentage rate of response as determined by complete cell-cycle arrest (CCCA, Ki76 ≤2.7) at week 2 by treatment arms. P value is calculated by Fisher exact test of a 1-sided hypothesis. D, Gene expression by MODAplex mRNA assay of cell cycle–associated genes at 2 weeks and EOT. P value compared abemaciclib-containing treatment arms versus anastrozole. E, CCAGs between resistant versus sensitive subgroups. All patients received anastrozole therapy for the 2 weeks of initial treatment, and then abemaciclib + anastrozole to the EOT. Plots show the expression of selected genes. Pairwise P values compare, respectively, the mean gene expression between (1/2/3): 1, abemaciclib + anastrozole-sensitive versus anastrozole-sensitive; 2, abemaciclib + anastrozole-sensitive versus abemaciclib + anastrozole-resistant; 3, anastrozole-sensitive versus abemaciclib + anastrozole-resistant. Baseline samples were pooled. F, CCAGs between intrinsically resistant versus sensitive tumor samples. Tumors were classified by posttreatment Ki67 expression as intrinsically resistant (Ki67 ≥7.4 at 2 weeks and EOT) or sensitive (Ki67 ≤2.7% at 2 weeks and EOT) to therapy regardless of initial 2 weeks of treatment. Baseline samples were pooled. Abbreviations: BL, baseline; n, tumor specimens; ns, nonsignificant (P > 0.05); *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; wks, weeks.

Figure 1.

Antiproliferative effects of abemaciclib, anastrozole (ANZ), and combination therapy on HR+/HER2− breast cancer. A, Individual paired Ki67 expression at baseline and 2 weeks after treatment with abemaciclib + ANZ, abemaciclib, and anastrozole. B, Geometric mean percentage suppression of Ki67 from baseline to 2 weeks by treatment arms. P values are based on a one-sided hypothesis test from a linear model with treatment, progesterone receptor status (positive vs. negative/unknown), and tumor size (<2 cm vs. ≥2 cm and <5 cm vs. ≥5 cm) as fixed effects. C, Mean percentage rate of response as determined by complete cell-cycle arrest (CCCA, Ki76 ≤2.7) at week 2 by treatment arms. P value is calculated by Fisher exact test of a 1-sided hypothesis. D, Gene expression by MODAplex mRNA assay of cell cycle–associated genes at 2 weeks and EOT. P value compared abemaciclib-containing treatment arms versus anastrozole. E, CCAGs between resistant versus sensitive subgroups. All patients received anastrozole therapy for the 2 weeks of initial treatment, and then abemaciclib + anastrozole to the EOT. Plots show the expression of selected genes. Pairwise P values compare, respectively, the mean gene expression between (1/2/3): 1, abemaciclib + anastrozole-sensitive versus anastrozole-sensitive; 2, abemaciclib + anastrozole-sensitive versus abemaciclib + anastrozole-resistant; 3, anastrozole-sensitive versus abemaciclib + anastrozole-resistant. Baseline samples were pooled. F, CCAGs between intrinsically resistant versus sensitive tumor samples. Tumors were classified by posttreatment Ki67 expression as intrinsically resistant (Ki67 ≥7.4 at 2 weeks and EOT) or sensitive (Ki67 ≤2.7% at 2 weeks and EOT) to therapy regardless of initial 2 weeks of treatment. Baseline samples were pooled. Abbreviations: BL, baseline; n, tumor specimens; ns, nonsignificant (P > 0.05); *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; wks, weeks.

Figure 2.

Ki67 expression and response by baseline tumor grade, PIK3CA mutation status, and gene expression analysis. A, Changes in Ki67 expression classified by baseline tumor grade. aPatient off treatment at EOT assessment. B, Changes in Ki67 expression classified by PIK3CA mutation status. C–E, RNA sequencing of baseline tumors: relative gene expression of RB1 (C) and CCNE1 (D) are reported in log2 (mean exon reads) scale; gene expression signature of Rb loss-of-function (E) is reported as RBsig score. Tumors were classified by treatment response at 2 weeks, defined by posttreatment Ki67 expression. Sensitive samples were defined as Ki67 ≤2.7% and resistant samples as Ki67 ≥7.4%. Abbreviations: ANZ, anastrozole; BL, baseline; CCNE1, Cyclin E1; GMR, geometric mean ratios; RB, retinoblastoma; RBsig, Rb-loss-of-function gene expression signature; wks, weeks.

Figure 2.

Ki67 expression and response by baseline tumor grade, PIK3CA mutation status, and gene expression analysis. A, Changes in Ki67 expression classified by baseline tumor grade. aPatient off treatment at EOT assessment. B, Changes in Ki67 expression classified by PIK3CA mutation status. C–E, RNA sequencing of baseline tumors: relative gene expression of RB1 (C) and CCNE1 (D) are reported in log2 (mean exon reads) scale; gene expression signature of Rb loss-of-function (E) is reported as RBsig score. Tumors were classified by treatment response at 2 weeks, defined by posttreatment Ki67 expression. Sensitive samples were defined as Ki67 ≤2.7% and resistant samples as Ki67 ≥7.4%. Abbreviations: ANZ, anastrozole; BL, baseline; CCNE1, Cyclin E1; GMR, geometric mean ratios; RB, retinoblastoma; RBsig, Rb-loss-of-function gene expression signature; wks, weeks.

Figure 3.

Combined treatment with abemaciclib and anastrozole (ANZ) downregulates cell-cycle processes and estrogen signaling and upregulates immune-response gene expression in HR+/HER2− early-stage breast cancer. A, Topmost enriched GSEA pathways across treatment arms and timepoints. *Nonsignificant effect. B, Heatmap of core-enriched genes in cell cycle–related and estrogen signaling gene sets. C, Heatmap of core-enriched genes in immune-related gene sets. Genes that were significantly differentially expressed across treatment arms and time points are shown in B and C. Abbreviations: wk, week. a2 weeks of initial therapy with abemaciclib followed by 14 weeks with combination therapy; b2 weeks of initial therapy with anastrozole followed by 14 weeks with combination therapy; c2 weeks of initial therapy with abemaciclib + anastrozole followed by 14 weeks with combination therapy.

Figure 3.

Combined treatment with abemaciclib and anastrozole (ANZ) downregulates cell-cycle processes and estrogen signaling and upregulates immune-response gene expression in HR+/HER2− early-stage breast cancer. A, Topmost enriched GSEA pathways across treatment arms and timepoints. *Nonsignificant effect. B, Heatmap of core-enriched genes in cell cycle–related and estrogen signaling gene sets. C, Heatmap of core-enriched genes in immune-related gene sets. Genes that were significantly differentially expressed across treatment arms and time points are shown in B and C. Abbreviations: wk, week. a2 weeks of initial therapy with abemaciclib followed by 14 weeks with combination therapy; b2 weeks of initial therapy with anastrozole followed by 14 weeks with combination therapy; c2 weeks of initial therapy with abemaciclib + anastrozole followed by 14 weeks with combination therapy.

Figure 3.

Combined treatment with abemaciclib and anastrozole (ANZ) downregulates cell-cycle processes and estrogen signaling and upregulates immune-response gene expression in HR+/HER2− early-stage breast cancer. A, Topmost enriched GSEA pathways across treatment arms and timepoints. *Nonsignificant effect. B, Heatmap of core-enriched genes in cell cycle–related and estrogen signaling gene sets. C, Heatmap of core-enriched genes in immune-related gene sets. Genes that were significantly differentially expressed across treatment arms and time points are shown in B and C. Abbreviations: wk, week. a2 weeks of initial therapy with abemaciclib followed by 14 weeks with combination therapy; b2 weeks of initial therapy with anastrozole followed by 14 weeks with combination therapy; c2 weeks of initial therapy with abemaciclib + anastrozole followed by 14 weeks with combination therapy.