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.

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.