Verzenio® (Abemaciclib)

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Abemaciclib: Biomarkers

Biomarkers analyzed in clinical trials with abemaciclib include mRNA, Ki67 expression, cell-cycle gene expression, PIK3CA, ESR1, TP53, EGFR, FGFR, NF1, MYC, and CCND1.

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MONARCH 3

MONARCH 3 was a randomized, double-blind, placebo-controlled, phase 3 study of abemaciclib or placebo with an NSAI (anastrozole or letrozole) in 493 postmenopausal women with HR+, HER2- advanced or MBC with no prior systemic treatment in this setting.1

Subgroup Analysis

In an exploratory subgroup analysis, biomarker analysis of baseline ctDNA was analyzed by the Guardant360 NGS-based assay to identify potential tumor-related (ie, somatic) genomic alterations in over 70 cancer related genes, including

  • point mutations (single-nucleotide variant)
  • indels
  • amplifications, and
  • fusions.2

Genomic alterations detected in baseline ctDNA were associated with clinical outcomes including PFS and ORR.2

Results

Baseline ctDNA results were available for 295 patients (201 abemaciclib; 94 placebo) with 83% of patients harboring 1 or more detectable genomic alterations.2

Commonly altered genes of interest (% frequency) detected in baseline ctDNA included

  • PIK3CA (38%)
  • TP53 (26%)
  • EGFR (15%)
  • FGFR1 (12%)
  • NF1 (12%)
  • MYC (9%)
  • CCND1 (9%), and
  • ESR1 (5%).2

Overall, patients treated with placebo plus NSAI who harbored detectable ctDNA genomic alterations had shorter median PFS compared to patients without detectable genomic alterations (14.9 months [95% CI: 11.0-23.1] vs 19.2 months [95% CI 9.4-NR]), as shown in Genomic Alterations in MONARCH 3.2

Genomic alterations in EGFR, FGFR1, MYC, and CCND1 were associated with median PFS <12 months with placebo plus NSAI. However, consistent with the ITT population, the addition of abemaciclib to NSAI benefitted these genomic subgroups regardless of ctDNA gene alterations.2

Genomic Alterations in MONARCH 32

Events,
n / N

Median PFS, Months
(95% CI)

Events,
n / N

Median PFS, Months
(95% CI)

HR
(95% CI)

Abemaciclib + NSAI

Placebo + NSAI

Overall

ITT population

170 / 328

28.2 (23.7-33.9)

123 / 165

14.8 (11.2-19.2)

0.52 (0.42-0.66)

TR populationa

93 / 201

38.7 (31.1-NR)

71 / 94

16.5 (11.7-23.1)

0.45 (0.33-0.61)

Any Gene Alteration

Detected

83 / 166

34.1 (27.2-40.0)

62 / 79

14.9 (11.0-23.1)

0.47 (0.34-0.66)

Not detected

10 / 35

NR (36.4-NR)

9 / 15

19.2 (9.40-NR)

0.31 (0.13-0.78)

TP53

Detected

29 / 53

27.0 (14.1-NR)

19 / 23

15.4 (5.7-30.4)

0.53 (0.30-0.95)

Not detected

64 / 148

39.9 (34.1-NR)

52 / 71

17.5 (11.7-24.2)

0.42 (0.29-0.60)

EGFR

Detected

10 / 26

NR (32.4-NR)

16 / 17

10.9 (2.1-24.7)

0.20 (0.09-0.47)

Not detected

83 / 175

36.4 (27.7-NR)

55 / 77

17.6 (14.6-25.5)

0.52 (0.37-0.73)

FGFR1

Detected

15 / 25

32.8 (10.1-NR)

10 / 11

7.6 (1.9-15.4)

0.37 (0.16-0.85)

Not detected

78 / 176

39.9 (31.1-NR)

61 / 83

19.2 (14.6-26.5)

0.45 (0.32-0.63)

NF1

Detected

10 / 24

35.9 (27-NR)

8 / 10

14.6 (1.6-33.4)

0.33 (0.13-0.84)

Not detected

83 / 177

38.7 (30.8-NR)

63 / 84

17.5 (11.7-24.2)

0.47 (0.33-0.65)

MYC

Detected

11 / 17

20.1 (5.5-NR)

9 / 10

6.5 (1.2-15.7)

0.33 (0.13-0.86)

Not detected

82 / 184

38.9 (32.9-NR)

62 / 84

19.2 (14.6-26.5)

0.45 (0.32-0.63)

CCND1

Detected

8 / 16

32.8 (5.5-NR)

10 / 10

7.2 (3.6-9.0)

0.28 (0.10-0.77)

Not detected

85 / 185

38.7 (31.1-NR)

61 / 84

17.6 (14.6-25.5)

0.48 (0.34-0.67)

Abbreviations: CCND1 = cyclin D1; ctDNA = circulating tumor DNA ; EGFR = epidermal growth factor receptor; FGFR1 = fibroblast growth factor receptor 1; HR = hazard ratio; ITT = intent-to-treat; MYC = v-myc avian myelocytomatosis viral oncogene homolog; NF1 = neurofibromatosis 1; NR = not reached; NSAI = nonsteroidal aromatase inhibitor; PFS = progression-free survival; TP53 = gene encoding tumor protein 53; TR = translational research.

aTR population consists of patients in the ITT population from whom a valid baseline ctDNA result has been obtained.

In contrast to prior studies, there was no subgroup (eg, patients harboring FGFR1 alterations) that did not derive benefit from abemaciclib, supporting the efficacy of abemaciclib, including in difficult to treat tumors. These findings are hypothesis-generating and warrant further investigations in clinical studies of CDK 4 and 6 inhibitors in combination with ET.2

MONARCH 2

MONARCH 2 was a randomized, double-blind, placebo-controlled, phase 3 trial of abemaciclib or placebo plus fulvestrant in 669 women with HR+, HER2- advanced breast cancer with disease progression following ET.3

The clinical significance of PIK3CA and ESR1 mutations from ctDNA and FFPE samples were analyzed using baseline plasma samples (n=334) and FFPE tumor samples (n=434) from 669 patients enrolled in MONARCH 2.4

RESULTS

PIK3CA mutations were detected in

  • 96 (40.3%) of 238 plasma samples, and
  • 133 (39.9%) of 333 FFPE samples.

H1047R was the most frequent mutation followed by E545K, E542K, and H1047L. The concordance of PIK3CA mutations in ctDNA and FFPE samples was 62.8%.4

ESR1 mutations were detected in

  • 190 (64.4%) of 295 plasma samples, and
  • 15 (4.4%) of 344 FFPE samples.4

The most frequent mutation was D538G followed by Y537C, Y537N, and Y537S. The concordance of ESR1 mutations in ctDNA and FFPE samples was 37.1%; this rate of detection of ESR1 mutations in ctDNA and FFPE samples is explained in part by the site of the biopsy (primary vs metastatic).4

Co-mutations in PIK3CA and ESR1 were observed in

  • 86 (36.1%) plasma, and
  • 5 (1.5%) FFPE samples.4

The relationship of PIK3CA and ESR1 mutation status and benefit from abemaciclib therapy were examined as shown in PIK3CA and ESR1 Mutation Status and Benefit in MONARCH 2.

PIK3CA and ESR1 Mutation Status and Benefit in MONARCH 24

 

Abemaciclib + Fulvestrant

Placebo + Fulvestrant

 

Mutation Status (Plasma)

n

Median PFS, Months (95% CI)

n

Median PFS (95% CI)

HR (95%)

PIK3CA wild-type

91

20 (14-NA)

51

12.7 (7.9-NA)

0.68 (0.42-1.09)

PIK3CA mutant

58

15 (9.4-NA)

38

5.7 (3.8-15)

0.46 (0.27-0.78)

ESR1 wild-type

72

16.3 (12.4-22.8)

33

11.6 (7.4-23.1)

0.69 (0.41-1.18)

ESR1 mutant

118

21.9 (15-NA)

72

10.3 (5.7-15.6)

0.49 (0.33-0.73)

Abbreviations: ESR1 = estrogen receptor gene; HR = hazard ratio; NA = not applicable; PFS = progression free survival; PIK3CA = phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.

The analysis showed PIK3CA and ESR1 mutations in ctDNA but not in archived FFPE samples correlated with response to abemaciclib, confirming the potential use of ctDNA analysis. The addition of abemaciclib to fulvestrant in MONARCH 2 demonstrated improvement in PFS regardless of PIK3CA or ESR1 status; however, the magnitude of benefit was numerically greater for patients with tumors harboring PIK3CA/ESR1 mutations.4

Exploratory Analysis PIK3CA Mutations

In an exploratory analysis, OS, TTC, and CFS was assessed in patients with and without PIK3CA mutation in MONARCH 2 using the Cox Interaction Model including treatment, PIK3CA mutant status, and treatment by PIK3CA interaction term.5

Results

Results of PIK3CA mutation status (E542K; E545K; H1047L; H1047R) from baseline ctDNA were available for 238 patients.5

Abemaciclib plus fulvestrant demonstrated a similar OS benefit for patients with PIK3CA mutation (HR=0.57; 95% CI: 0.34-0.96) and for patients with PIK3CA wild-type (HR=0.56; 95% CI: 0.34-0.91) compared with placebo plus fulvestrant.5

Median TTC and CFS were longer in the abemaciclib plus fulvestrant arm compared with the placebo plus fulvestrant arm both in patients with detectable PIK3CA mutation and in patients without PIK3CA mutation, as shown in Patients With and Without PIK3CA Mutation in MONARCH 2.5

Patients With and Without PIK3CA Mutation in MONARCH 25

 

PIK3CA Mutant

PIK3CA Wild-Type

 

 

Abemaciclib +Fulvestrant

(n=58)

Placebo + Fulvestrant

(n=38)

HR (95% CI)

Abemaciclib + Fulvestrant

(n=91)

Placebo + Fulvestrant

(n=51)

HR (95% CI)

Interaction P Value

OS Median, mo (95% CI)

44.5 

(31.0-NR)

 

33.8 

(24.2-41.7)

 

0.57

(0.34-0.96)

 

55.5 

(47.7-55.5)

41.7 

(29.4-49.7)

0.56

(0.34-0.91)

.949

TTC Median, mo (95% CI)

39.2 

(24.6-NR)

 

19.2 

(6.7-NR)

 

0.65

(0.37-1.18)

 

NR

(34.3-NR)

19.2 

(12.0-31.1)

0.50

(0.31-0.78)

.463

CFS Median, mo (95% CI)

25.8 

(16.0-42.1)

 

12.8 

(5.2-33.2)

 

0.63

(0.39-1.03)

 

36.9 

(20.7-NR)

19.2 

(12.0-29.4)

0.53

(0.35-0.80)

.588

Abbreviations: CFS = chemotherapy-free survival; HR = hazard ratio; NR = not reached; OS = overall survival; PIK3CA = phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; TTC = time to chemotherapy.

Conclusions

In this exploratory analysis of MONARCH 2, abemaciclib plus fulvestrant demonstrated benefit in OS, TTC, and CFS in patients with and without PIK3CA mutations.5

More detailed information is found in the MONARCH 2 PIK3CA Video.

MONARCH 1

MONARCH 1 was a phase 2, single-arm study which evaluated safety and efficacy of abemaciclib as monotherapy in 132 women with refractory HR+, HER2- advanced or MBC whose disease progressed on or after both ET and chemotherapy.6

As an exploratory objective, blood and tissue samples for biomarker research were collected from a subset of patients (n=77) to explore biomarkers related to the Rb pathway, CDK 4 and 6, the cell cycle, and pathogenesis of breast cancer.7

Tumor tissues collected at baseline were assayed for mRNA expression of cell-cycle related genes using a novel automated multimodal multiplexed platform (Modaplex, QIAGEN); normal breast tissues from reduction mammoplasty patients were analyzed for comparison.7

This exploratory biomarker analysis showed mRNA profiles from tumor and normal breast tissues align with known biology. The analysis also showed changes in mRNA expression of cell-cycle related genes including inhibition of proliferation genes after 14 days of abemaciclib treatment. This reversed upon cessation of treatment with abemaciclib. Higher tissue levels of RB1 mRNAs were also correlated with clinical outcomes. However, since MONARCH 1 is a single-arm study, the biomarker effect cannot be considered prognostic or predictive. Further exploration of the predictive value of baseline tumor mRNA and/or change in plasma exosome mRNA for patients receiving abemaciclib is underway.7

neoMONARCH

neoMONARCH was a randomized, open-label, phase 2 neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2- breast cancer.8,9

Methods

Patients were randomized to 1 of 3 trial arms for the first 2 weeks of therapy

  • abemaciclib monotherapy
  • abemaciclib plus anastrozole, or
  • anastrozole monotherapy.8,9

Abemaciclib was initiated at 150 mg orally every 12 hours and anastrozole at 1 mg orally daily. Loperamide 2 mg was administered prophylactically with each abemaciclib dose for the first 28 days, then at the discretion of the investigator.8,9

The primary objective of the study was to compare the change from baseline in Ki67 expression, a proliferation marker observed in breast cancer tissue samples, after 2 weeks of therapy. To evaluate Ki67 expression, patients received a biopsy at baseline prior to randomization and after 2 weeks of treatment. All patients received 2 weeks of initial therapy followed by 14 to 22 weeks of treatment with abemaciclib plus anastrozole with the option of surgery afterwards.8,9

Ki67 Results

Abemaciclib alone or in combination with anastrozole significantly reduced Ki67 expression compared to anastrozole alone after 2 weeks of treatments as seen in neoMONARCH Ki67 Results After 2 Weeks of Therapy. A total of 167 patients were evaluable for the primary objective. The ORR following 16 weeks of therapy was 46% measured radiologically per RECIST, and 54% measured by caliper per RECIST for the 224 randomized patients. Complete pathologic response was documented in 7 (4%) of the 190 patients that underwent surgery.8,9

neoMONARCH Ki67 Results After 2 Weeks of Therapy8,9

 

Abemaciclib + Anastrozole
n=59

Abemaciclib Monotherapy
n=52

Anastrozole Monotherapy
n=56

Geometric mean change in Ki67, %

-93

-91

-63

P value

<.001

Ki67 respondersa, n

40

30

8

Patients with tumors exhibiting CCCAb, %

68

58

14

P value

<.001

Abbreviation: CCCA = complete cell cycle arrest.

aKi67 index ≤2.7% at 2 weeks.

b47% of tumors demonstrated CCCA.

A subgroup analysis showed that abemaciclib-driven change in Ki67 was not associated with disease stage, baseline lymph node involvement, tumor grade, tumor size, or PIK3CA mutation status.8,9

Separately, a meta-analysis of 7 randomized trials of systemic therapies in postmenopausal women with HR+ breast cancer reporting Ki67 reduction in the neoadjuvant setting suggested that Ki67 correlates with (neo)adjuvant disease-free survival and has potential utility as a surrogate endpoint to screen and prioritize experimental regimens for development in the adjuvant setting.10

Markers of Resistance and Sensitivity

In an exploratory analysis of neoMONARCH, cell-cycle gene expression was analyzed to determine markers of sensitivity and resistance to therapy.11

Anastrozole-treated tumors that did not achieve cell-cycle arrest at 2 weeks (n=8) displayed higher expression of the cell-cycle associated genes

  • FOXM1
  • E2F1
  • TOPO2A, and
  • RRM2.11

The addition of abemaciclib to anastrozole decreased gene expression in a majority of the tumors (n=5, 62.5%). Tumors intrinsically resistant to treatment with abemaciclib and anastrozole displayed persistently elevated levels of cell-cycle associated genes compared to sensitive tumors. Finally, gene expression signature of Rb loss-of-function and RB1 gene expression levels were associated with sensitivity to abemaciclib.11

Modulation of Immune Response

In an exploratory analysis of neoMONARCH, the early and late immune-modulating effects of abemaciclib were evaluated.12

Consistent with the known activity of abemaciclib to inhibit the cell cycle, significant treatment induced downregulation of genes was observed related to

  • mitotic spindle organization
  • replication stress response
  • G2M checkpoint, and
  • E2F targets.12

Abemaciclib treatment for 2 weeks, alone or in combination with anastrozole, followed by 14 weeks of combination therapy was associated with upregulation of gene expression signatures related to T-cell immune response and antigen presentation. Importantly, this phenomenon was not observed with 2 weeks of anastrozole treatment alone followed by 14 weeks of combination therapy.12

These data lend support that continuous inhibition of CDK 4 and 6 signaling by abemaciclib treatment leads to prolonged cell-cycle arrest resulting in tumor cell apoptosis and senescence, which then leads to enhanced immune activation.12

nextMONARCH 1

nextMONARCH 1 was a phase 2, randomized, open-label trial of abemaciclib with or without tamoxifen in women with HR+, HER2- advanced or MBC who progressed on prior ET and chemotherapy.13-15

Methods

Patients were stratified by liver metastases and prior use of tamoxifen in the advanced setting and randomized 1:1:1 to

  • arm A: abemaciclib 150 mg every 12 hours plus tamoxifen 20 mg every day 
  • arm B: abemaciclib 150 mg every 12 hours as monotherapy, or
  • arm C: abemaciclib 200 mg every 12 hours plus prophylactic loperamide.14

Prophylactic loperamide 2 mg daily was administered during cycle 1 and then at the investigator's discretion.14,15

Available baseline plasma samples for patients in the abemaciclib monotherapy arms (n=146; 94%) were analyzed by the Guardant360 NGS-based assay to identify potential tumor-related (ie, somatic) genomic alterations in the over 70 cancer-related genes including

  • point mutations (single-nucleotide variant)
  • indels
  • amplifications, and
  • fusions.15

Results

The majority of patients (91%) receiving abemaciclib monotherapy had a least 1 genomic alteration detected in baseline ctDNA.15

The ITT population and the translational research population had similar treatment benefit (7.4 months [95% CI: 5.5-9.1] vs 7.4 months [95% CI: 5.5-9.1]; p=.945).15

The most frequently altered genes detected in baseline ctDNA included

  • ESR1 (41%)
  • PIK3CA (35%)
  • TP53 (29%)
  • FGFR1 (23%)
  • GATA3 (20%), and
  • MYC (20%).15

Overall, patients with any detectable ctDNA genomic alterations generally had a shorter median PFS compared to patients without any detectable genomic alterations (6.8 months [95% CI: 5.2-9.0] vs 12.0 months [95% CI: 5.4-23.9]; p=.099).15

In particular, genomic alterations in PIK3CA, TP53, FGFR1, MYC, NF1, EGFR, ERBB2, or CCNE1 were associated with a significantly shorter median PFS in this heavily pretreated patient population. Patients with detected alterations RB1 or ESR1 trended towards a shorter median PFS, while patients with detected alterations in GATA3 trended towards a longer median PFS.15

Conclusions

This is the first exploratory study to evaluate the genomic markers of response to monotherapy CDK 4 and 6 inhibitor in a heavily pretreated patient population with HR+, HER2- ABC. The authors concluded these results provide insight into the genomic landscape of ABC and, if validated, could inform further trials of CDK 4 and 6 inhibitors.15

MONARCH 3 and nextMONARCH 1 - Additional Analyses

Plasma from patients in the abemaciclib or placebo + AI arms (MONARCH 3) or abemaciclib monotherapy arms (nextMONARCH 1) was analyzed by the Guardant360 assay to identify potential tumor-related genomic alterations including point mutations, indels, amplifications, and fusions acquired at end of treatment in comparison with baseline.16

MONARCH 3 Results

In the abemaciclib + AI arm in MONARCH 3, commonly acquired alterations at end of treatment included 

  • ESR1 (17%)
  • TP53 (10%)
  • EGFR (8%)
  • FGFR1 (7%), and
  • PDGFRA (7%).16

In the placebo + AI arm, commonly acquired alterations at end of treatment included 

  • ESR1 (31%)
  • TP53 (10%), and
  • BRCA1 (7%).16

Acquired alterations were more frequent for abemaciclib + AI patients compared to 0% in the placebo + AI arm (p=.008 RB1; p=.015 MYC or AR) and included 

  • RB1 (6%)
  • MYC (5%), and
  • AR (5%).16

In contrast, acquired ESR1 alterations were less frequent with abemaciclib + AI vs placebo + AI (17% vs 31%, p=.038). 16

nextMONARCH 1 Results

In nextMONARCH 1, the most commonly acquired alterations with abemaciclib monotherapy were in 

  • TP53 (10%)
  • EGFR (9%)
  • RB1 (9%)
  • MYC (9%), and
  • MET (8%).16

In addition, acquired alterations in ESR1 (6%) and AR (3%) were also found.16

PIK3CA alterations were not frequently acquired (abemaciclib + AI 1%, placebo + AI 6%, abemaciclib monotherapy 5%). 16

Conclusions

Acquired genomic alterations potentially associated with emerging mechanisms of resistance to abemaciclib alone or in combination with AI may include RB1, MYC, or AR alterations, while the acquisition of ESR1 alterations was less common in patients treated with abemaciclib + AI compared to placebo + AI. These findings are hypothesis-generating and provide insight into mechanisms of resistance to abemaciclib vs ET.16

More detailed information is found in the Acquired Genomic Alterations in Circulating Tumor DNA Video.

Referencias

1Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646. https://doi.org/10.1200/jco.2017.75.6155

2Goetz M, Beck J, Campone M, et al. Efficacy of abemaciclib based on genomic alterations detected in baseline circulating tumor DNA from the MONARCH 3 study of abemaciclib plus nonsteroidal aromatase inhibitor. Poster presented at: 42nd Annual San Antonio Breast Cancer Symposium (SABCS); December 10-14, 2019; San Antonio, TX. https://www.abstractsonline.com/pp8/#!/7946/presentation/1957

3Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-2884. http://dx.doi.org/10.1200/JCO.2017.73.7585

4Tolaney S, Toi M, Neven P, et al. Clinical significance of PIK3CA and ESR1 mutations in ctDNA and FFPE samples from the MONARCH 2 study of abemaciclib plus fulvestrant. Talk presented at: 110th Annual Meeting of the American Association for Cancer Research (AACR); March 29-April 3, 2019; Atlanta, GA.

5Tolaney S, Toi M, Neven P, et al. Clinical outcomes of patients with PIK3CA mutations in circulating tumor DNA: update from the MONARCH 2 study of abemaciclib plus fulvestrant. Poster presented at: 111th Annual Meeting of the American Association for Cancer Research (AACR Virtual); June 22-24, 2020. Accessed May 15, 2020. https://www.abstractsonline.com/pp8/#!/9045/presentations/abemaciclib/1

6Dickler MN, Tolaney SM, Rugo HS, et al. 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. Clin Cancer Res. 2017;23(17):5218-5224. http://dx.doi.org/10.1158/1078-0432.CCR-17-0754

7Tolaney SM, Cortés J, Dickler MN, et al. Exploratory biomarkers in MONARCH 1, a phase II study of abemaciclib monotherapy in hormone-receptor positive (HR+) HER2- metastatic breast cancer (MBC). Ann Oncol. 2016;27(suppl 6):LBA12. https://doi.org/10.1093/annonc/mdw435.01

8Martin M, Hurvitz S, Chan D, et al. Final results of NeoMONARCH: a phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive, HER2 negative breast cancer. Poster presented at: 40th Annual San Antonio Breast Cancer Symposium (SABCS); December 5-9, 2017; San Antonio, TX. http://sabcs17.posterview.com/nosl/i/PD5-01

9Hurvitz S, Martin M, Press M, et al. Potent cell cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase 2 neoadjuvant study in HR+/HER2- breast cancer. Clin Cancer Res. 2020:26(3):566-580. https://doi.org/10.1158/1078-0432.Ccr-19-1425

10Johnston S, Frenzel M, Thomas ZM, et al. A multi-study correlative analysis of change in Ki67 in the neoadjuvant setting and disease-free survival improvement in the adjuvant setting. Poster presented at: 40th Annual San Antonio Breast Cancer Symposium (SABCS); December 5-9, 2017; San Antonio, TX. http://sabcs17.posterview.com/nosl/i/P4-09-01

11Hurvitz S, Martin M, Wijayawardana S, et al. Markers of response to CDK4 & 6 inhibition from neoMONARCH: a phase II neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive, HER2- negative breast cancer. Poster presented at: 41st Annual San Antonio Breast Cancer Symposium (SABCS); December 4-8, 2018; San Antonio, TX. http://sabcs18.posterview.com/nosl/i/P3-10-08

12Hurvitz S, Martin M, Press MF, et al. Treatment with abemaciclib modulates the immune response in gene expression analysis of the neoMONARCH neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer. Poster presented at: 41st Annual San Antonio Breast Cancer Symposium (SABCS); December 4-8, 2018; San Antonio, TX. http://sabcs18.posterview.com/nosl/i/PD2-10

13A study of abemaciclib (LY2835219) plus tamoxifen or abemaciclib alone in women with metastatic breast cancer (nextMONARCH 1). ClinicalTrials.gov Identifier: NCT02747004. Updated November 16, 2020. Accessed December 10, 2020. https://clinicaltrials.gov/show/NCT02747004

14Hamilton E, Cortes J, Dieras V, et al. nextMONARCH 1: phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer. Poster presented at: 41st Annual San Antonio Breast Cancer Symposium (SABCS); December 4-8, 2018; San Antonio, TX. Accessed December 10, 2020. https://sabcs18.posterview.com/nosl/i/PD1-11

15Hamilton E, Cortes J, Jerusalem G, et al. Genomic markers of response to monotherapy abemaciclib in the nextMONARCH 1 study. Poster presented at: 111th Annual Meeting of the American Association for Cancer Research (AACR Virtual); June 22-24, 2020. Accessed May 15, 2020. https://www.abstractsonline.com/pp8/#!/9045/presentations/abemaciclib/1

16Goetz M, Hamilton E, Campone M, et al. Acquired genomic alterations in circulating tumor DNA from patients receiving abemaciclib alone or in combination with endocrine therapy. Poster presented at: 56th Annual Meeting of the American Society of Clinical Oncology (ASCO Virtual); May 29-May 31, 2020. Accessed May 21, 2020. https://meetinglibrary.asco.org/record/185090/abstract

Glossary

ABC = advanced breast cancer

AI = aromatase inhibitor

AR = androgen receptor

BRCA1 = breast cancer susceptibility gene 1

CCND1= cyclin D1

CCNE1 = cyclin E1

CDK = cyclin-dependent kinase

CFS = chemotherapy-free survival

ctDNA = circulating tumor DNA

E2F1 = E2F transcription factor 1

EGFR = epidermal growth factor receptor

ERBB2 = erb-b2 receptor tyrosine kinase 2

ESR1 = estrogen receptor gene

ET = endocrine therapy

FFPE = formalin-fixed paraffin-embedded

FGFR1 = fibroblast growth factor receptor 1

FOXM1 = forkhead box protein M1

GATA3 = GATA binding protein 3

HER2- = human epidermal growth factor receptor 2-negative

HR = hazard ratio

HR+ = hormone receptor-positive

ITT = intent-to-treat

MBC = metastatic breast cancer

MET = MET proto-oncogene

mRNA = messenger RNA

MYC = v-myc avian myelocytomatosis viral oncogene homolog

NF1 = neurofibromatosis 1

NGS = next-generation sequencing

NR = not reached

NSAI = nonsteroidal aromatase inhibitor

ORR = objective response rate

OS = overall survival

PDGFRA = platelet-derived growth factor receptor alpha

PFS = progression-free survival

PIK3CA = phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

RB1 = retinoblastoma 1

RECIST = Response Evaluation Criteria in Solid Tumors

RRM2 = ribonucleotide reductase subunit M2

TOPO2A = DNA topoisomerase II alpha

TP53 = gene encoding tumor protein 53

TTC = time to chemotherapy

Fecha de la última revisión: 2020 M06 11


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