Verzenio® (Abemaciclib)

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Abemaciclib: Ethnicity Efficacy and Safety

Preplanned subgroup analyses were performed for racial subgroups in the MONARCH 2, MONARCH 3, and MONARCH plus study of abemaciclib in breast cancer.

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Efficacy and Safety

Abemaciclib in Combination With an NSAI (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

The majority of the patients in the study were

  • Caucasian (58.4%)
  • Asian (30.0%), or
  • Black or African American (1.6%).2

In the MONARCH 3 study, preplanned subgroup analyses were performed for race (Caucasian, Asian, and other).2 Overall, a PFS benefit was demonstrated across all prespecified subgroups. However, a greater PFS HR was observed in the Asian population than in the Caucasian population.1 This difference in PFS treatment effect was primarily driven by the reduced performance of the control arm in Asian patients.2

In both the ITT and measurable disease populations, the treatment effect on ORR was similar for Asian and Caucasian patients. Overall survival results for each preplanned subgroup are not available due to the immaturity of the data.2

Asian patients had a higher incidence of grade ≥3 neutropenia, grade ≥3 neutrophil count decreased, grade ≥3 anemia, grade ≥3 abnormal liver tests, and pneumonitis compared to other race subgroups as seen in Adverse Events and Lab Abnormalities in Abemaciclib Arm by Race Subgroups in MONARCH 3.2

Caucasian patients had a higher incidence of grade ≥3 diarrhea compared to other patients and Asian patients.2

Five Asian and 3 Caucasian patients discontinued any study drug due to events of neutropenia and for 1 patient, race was not reported. Two patients who discontinued any study drug due to events of diarrhea were Asian, and 4 patients were Caucasian. Seven patients who discontinued any study drug due to hepatic events were Asian and 3 patients were Caucasian.2

No major differences in the incidence of increased blood creatinine, overall infections and infestations system organ class, or increased bilirubin were observed between race subgroups.2

Adverse Events and Lab Abnormalities in Abemaciclib Arm by Race Subgroups in MONARCH 32

Adverse Event, %

Asian
n=103

Caucasian
n=186

Other
n=11

Neutropenia, grade ≥3

27.2

16.8

27.3

Neutrophil count decreased, grade ≥3

31.0

20.0

18.3

Anemia, grade ≥3

9.7

3.8

9.1

ALT TEAEs

12.6

3.2

0

ALT laboratory abnormality

14.9

2.9

0

AST TEAEs

7.8

1.6

0

AST laboratory abnormality

9.9

1.1

0

Pneumonitis, any grade

4.9

1.1

0

Diarrhea, grade ≥3

4.9

11.9

9.1

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; TEAEs = treatment-emergent adverse events.

Abemaciclib in Combination With Fulvestrant (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 majority of the patients in the study were

  • Caucasian (55.8%)
  • Asian (32.0%)
  • American Indian or Alaska native (3.9%), or
  • Black or African American (2.1%).2

In the MONARCH 2 study, preplanned subgroup analyses were performed for race (Caucasian, Asian, and other). The PFS treatment effect of abemaciclib plus fulvestrant was consistent across these subgroups. Overall survival results for each preplanned subgroup are not yet available due to immaturity of the data.2

In the ITT population, 212 Asian patients were randomized to abemaciclib plus fulvestrant (n=147) or placebo plus fulvestrant (n=65). At data cutoff, 89 OS events were observed in Asian patients with

  • median OS not reached for abemaciclib plus fulvestrant and 48.9 months for placebo plus fulvestrant (HR=0.798; 95% CI: 0.515-1.235; p=.38), and
  • OS rates at 42 months were 64% (95% CI: 55.5-71.8) for abemaciclib plus fulvestrant and 53% (95% CI: 39.9-64.6) for placebo plus fulvestrant.4

Additional efficacy data on Asian patients who received abemaciclib plus fulvestrant can be seen in PFS2, TTC, and CFS in Asian ITT Population of MONARCH 2.

PFS2, TTC, and CFS in Asian ITT Population of MONARCH 24

ABE + FULV (n=147)


PFS2

TTC

CFS

HR (95% CI)

0.588 (0.420-0.823)

0.601 (0.411-0.877)

0.573 (0.402-0.815)

P value

.001

.008

.002

Abbreviations: ABE = abemaciclib; CFS = chemotherapy-free survival; FULV = fulvestrant; HR = hazard ratio; ITT = intent to treat; PFS2 = progression-free survival 2; TTC = time to chemotherapy.

Asian patients had a higher incidence of grade ≥3 neutropenia, grade ≥3 neutrophil count decreased, and grade ≥3 abnormal liver tests compared to other race subgroups as seen in Adverse Events and Lab Abnormalities in Abemaciclib Arm by Race Subgroups in MONARCH 2.2

Five Asian patients and 5 non-Asian patients discontinued abemaciclib or all study treatment (2 patients who discontinued all study treatment were in the placebo plus fulvestrant arm) due to AEs of elevated hepatic transaminases, bilirubin, alkaline phosphatase, or gamma-glutamyltransferase.2

No major differences in the incidence of AEs of diarrhea, increased blood creatinine, increased and overall infections and infestations system organ class, or in the incidence of laboratory abnormalities of creatinine increased were observed.2 The safety profile was consistent with previously reported safety data in Asian patients.4

Adverse Events and Lab Abnormalities in Abemaciclib Arm by Race Subgroups in MONARCH 22

Adverse Event, %

Asian
n=148

Caucasian
n=234

Other
n=28

Neutropenia, grade ≥3

44.6

17.5

17.9

Neutrophil count decreased, grade ≥3

50.4

23.4

32.2

ALT TEAEs

6.8

2.1

7.1

ALT laboratory abnormality

6.9

2.2

7.1

AST TEAEs

4.7

1.3

0

AST laboratory abnormality

6.9

2.2

0

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; TEAEs = treatment-emergent adverse events.

Abemaciclib Administered as a Single Agent (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.5

The majority of the patients in the study were

  • Caucasian (84.8%)
  • Black or African American (4.5%), or
  • Asian (1.5%).2

Due to the small sample size of the other race subgroups in the MONARCH 1 study, subgroup analyses based on race for efficacy or safety were not conducted.2

Abemaciclib in Combination With NSAI or Placebo and to Compare Fulvestrant Plus Abemaciclib or Plus Placebo (MONARCH plus)

MONARCH plus was a phase 3 randomized, double-blind, placebo-controlled study that compared anastrozole or letrozole plus abemaciclib or placebo (cohort A; n=306), and compared fulvestrant plus abemaciclib or placebo (cohort B; n=157) in postmenopausal women with HR+, HER2- ABC (NCT02763566). The primary objective was PFS in cohort A and the key secondary objective was PFS in cohort B.6

MONARCH plus was designed to prospectively assess the efficacy and safety profile of abemaciclib in patient populations from China, Brazil, India, and South Africa.6

The majority of patients in cohort A were 

  • Asian (88.6%%)
  • Caucasian (10.5%), or
  • Black or African (1.0%).2

The majority of patients in cohort B were

  • Asian (90.4%)
  • Caucasian (7.6%)
  • Black or African (1.3%), or
  • Multiple (0.6%).2 

In the MONARCH plus study, preplanned subgroup analyses were performed for country (China vs. non-China).2 The PFS treatment effect of abemaciclib was consistent overall across patient subgroups in both cohorts. Benefit was not observed in subgroups of patients from non-China sites, aged ≥65 years, or with de novo metastatic disease in cohort A. Overall survival results for each preplanned subgroup are not yet available due to immaturity of the data.6

The safety profile for both abemaciclib cohorts was consistent with previous reports for abemaciclib plus ET, and the most commonly reported AEs were similar between the MONARCH plus study and MONARCH 2 and MONARCH 3 trials.6,7

Abemaciclib plus NSAI or fulvestrant showed statistically significant and clinically meaningful improvement in PFS and ORR in predominantly Asian HR+/HER2- ABC patients with no new safety signals observed. MONARCH plus analysis demonstrated efficacy benefit consistent with the MONARCH 2 and MONARCH 3 trials.6

Abemaciclib Monotherapy Phase 1 Trial in Native Chinese Patients

A phase 1, randomized, open-label trial was conducted in Native Chinese patients with advanced and/or metastatic cancers. Patients were randomized to receive abemaciclib 150 mg or 200 mg orally every 12 hours on a 28-day cycle.8

The primary objective was to evaluate the safety and tolerability of abemaciclib monotherapy. The secondary objective was to assess PK and antitumor activity.8

Results

A total of 25 patients were treated with abemaciclib

  • 12 patients in the 150 mg cohort, and
  • 13 patients in the 200 mg cohort.8

Patients had a median age of 54 years (range: 29-69) and a median of 4 prior systemic therapies (range: 1-7) for metastatic disease.8

No CR was observed. Two patients (8%) achieved PR with 1 confirmed responder. The DCR (CR + PR + SD) was 68% (n=17).8

The majority of TEAEs were grade 1 or 2 in severity. In 2 dose cohorts, common (≥25%) TEAEs related to study treatment included

  • diarrhea
  • neutrophil count decreased
  • WBC count decreased
  • decreased appetite
  • blood creatinine increased
  • malaise
  • anemia
  • platelet count decreased
  • nausea
  • ALT increased, and
  • cough.8

Study treatment related grade ≥3 TEAE (≥10%) included

  • neutrophil count decreased (32%)
  • platelet count decreased (24%)
  • embolism (16%)
  • diarrhea (12%), and
  • WBC count decreased (12%).8

Four patients (16%) discontinued treatment due to an AE.8

The PK characteristics of abemaciclib and its 2 major active metabolites (LSN2839567 and LSN3106726) were comparable to those observed in previous studies in non-Chinese populations.8

Conclusions

Abemaciclib was well tolerated at both cohorts evaluated in Chinese patients with advanced and/or metastatic cancers. The safety profile and PK characteristics in Chinese patients were similar to those in previous studies in non-Chinese populations. Preliminary antitumor activity was observed and supported further development of abemaciclib in Chinese patients.8

Japanese Study – Preferences for Treatment

A Japanese study was conducted to identify factors that affect preferences for treatment of breast cancer patients and understand their relative importance. The study explored whether patients’ sociodemographic and clinical characteristics would affect patient preference in choice of treatment.9

A questionnaire for discrete choice experiment was developed and composed of 9 choice sets containing 5 attributes with different levels including

  • PFS
  • incidence of diarrhea
  • frequency of diarrhea (increase in the number of stools per day than usual)
  • duration of diarrhea, and
  • route and frequency of administration.9

Of 302 respondents recruited, 258 had valid responses. The mean age was 56.7 years, 47.7% had paid employment, median duration since diagnosis was 5.1 years, and 98.1% had experienced hormonal therapy.9

According to the absolute magnitude of coefficients, when the frequency of diarrhea is 6, the order of attributes’ relative importance was 

1. PFS

2. duration of diarrhea

3. frequency of diarrhea

4. incidence of diarrhea, and

5. route and frequency of administration.9

However, when the frequency of diarrhea becomes 9, frequency of diarrhea was the most important attribute for patients.9

All tested attributes were statistically significant (p<.0001) on their preference in choice of treatment. When patient-specific covariates were included in the model, the patients who have experienced relapse or metastasis showed the strongest preference for the longest PFS (16 months) and patients who were 45 to 59 years old showed the weakest preference for the highest frequency of diarrhea at 9.9

Postmenopausal and HR+ breast cancer patients in Japan showed preference for treatments which can extend PFS even with the potentiality of grade 2 diarrhea. This study also showed that patients’ sociodemographic and clinical characteristics tend to affect patients’ treatment choices.9

References

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

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

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

4Huang CS, Toi M, Im YH, et al. Abemaciclib plus fulvestrant in east Asian women with HR+, HER2- advanced breast cancer: overall survival from MONARCH 2. Paper presented at: 1st European Society for Medical Oncology (ESMO) Asia Virtual Congress; November 20-22, 2020. Accessed November 17, 2020. https://oncologypro.esmo.org/meeting-resources/esmo-asia-virtual-congress-2020/abemaciclib-plus-fulvestrant-in-east-asian-women-with-hr-her2-advanced-breast-cancer-overall-survival-from-monarch-2

5Dickler 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

6Zhang QY, Sun T, Yin YM, et al. MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2– advanced breast cancer: the multinational randomized phase III study. Ther Adv Med Oncol. 2020;12:1-14. https://doi.org/10.1177/1758835920963925

7Jiang Z, Hu X, Zhang Q, et al. Management of abemaciclib associated diarrhea in patients with hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: analysis of the MONARCH plus study. Paper presented at: 43rd Annual San Antonio Breast Cancer Symposium (SABCS); December 8-11, 2020; San Antonio, TX. Accessed November 17, 2020. Abstract PS13-25 https://www.sabcs.org/Portals/SABCS2016/2020%20SABCS/ALL%20ABSTRACTS%202-9.pdf?ver=2020-12-09-104626-337

8Hu X, Yang N, Zhang J, et al. A phase 1 study of abemaciclib in Chinese patients with advanced and/or metastatic cancers. 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

9Omori Y, Enatsu S, Cai Z, et al. Patients’ preferences for postmenopausal HR+ HER2- advanced breast cancer treatments in Japan. Poster presented at: 41st Annual San Antonio Breast Cancer Symposium (SABCS); December 4-8, 2018; San Antonio, TX. https://www.abstracts2view.com/sabcs18/view.php?nu=SABCS18L_545&terms=

Glossary

ABC = advanced breast cancer

AE = adverse event

ALT = alanine aminotransferase 

CFS = chemotherapy-free survival

CR = complete response

DCR = disease control rate

ET = endocrine therapy

HER2- = human epidermal growth factor receptor 2-negative

HR = hazard ratio

HR+ = hormone receptor-positive

ITT = intent-to-treat

MBC = metastatic breast cancer

NSAI = nonsteroidal aromatase inhibitor

ORR = objective response rate

OS = overall survival

PFS = progression-free survival

PFS2 = progression-free survival 2

PK = pharmacokinetic(s)

PR = partial response

SD = stable disease

TEAE = treatment-emergent adverse event

TTC = time to chemotherapy

WBC = white blood cell

Fecha de la última revisión: 2020 M10 19


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