Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer

Warren Han, Mercer University College of Pharmacy

Cyclin-dependent kinases (CDK) are enzymes which play a role in cell cycle regulation.  However, dysregulated cyclin D1:CDK4/6 complexes are seen in both the initiation and the progression of certain cancers.  The discovery of this mechanism has led to more research on CDK4/6 inhibitors. [1]

Breast cells have hormone receptors (HR) that pair to either estrogen or progesterone to promote normal cell proliferation.  Mutations in these receptors are stated to lead to the growth and spread of breast cancer cells.  It has been determined that roughly two out of three breast cancers test positive for hormone receptors. [2]

Human epidermal growth factor receptor 2 (HER2) is a gene that encodes for protein receptors on breast cells, which regulate how a healthy breast cell grows, divides, and repairs itself.  If the HER2 gene is mutated, breast cancer cells are more likely to spread, recur, and grow faster in an uncontrolled manner. [3]

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer [4]
Design Randomized, placebo-controlled, phase 3 trial; N= 668
Objective To evaluate the efficacy and safety of ribociclib combined with letrozole for treatment in metastatic breast cancer
Study Groups Ribociclib (N= 334); placebo (N= 334)
Methods Postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease were randomly assigned to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole.
Duration January 24, 2014 to March 24, 2015
Primary Outcome Measure 18-month progression-free survival rate
Baseline Characteristics   Ribociclib Group, n (%) Placebo Group, n (%)
Median age (range), years 62 (23-91) 63 (29-88)
White 269 (80.5) 280 (83.8)
Asian 28 (8.4) 23 (6.9)
Black 10 (3.0) 7 (2.1)
Other or Unknown 27 (8.1) 24 (7.2)
Cancer Stage III 1 (0.3) 3 (0.9)
Cancer Stage IV 333 (99.7) 331 (99.1)
Estrogen-receptor positive 332 (99.4) 333 (99.7)
Progesteron-receptor positive 271 (81.1) 278 (83.2)
Newly diagnosed disease 114 (34.1) 113 (33.8)
Existing disease 220 (65.9) 221 (66.2)
≤ 12 mo 4 (1.2) 10 (3.0)
>12 to ≤ 24 mo 14 (4.2) 15 (4.5)
>24 mo 202 (60.5) 195 (58.4)
Neoadjuvant or adjuvant chemotherapy 146 (43.7) 145 (43.4)
Neoadjuvant or adjuvant endocrine therapy 175 (52.4) 171 (51.2)
Anastrozole 47 (14.1) 42 (12.6)
Exemestane 19 (5.7) 25 (7.5)
Goserelin 6 (1.8) 3 (0.9)
Letrozole 34 (10.2) 25 (7.5)
Tamoxifen 140 (41.9) 145 (43.4)
Other 2 (0.6) 4 (1.2)
Results Ribociclib Placebo
18-month progression-free survival rate 63%

(95% confidence interval 54.6 to 70.3)

42.2%

(95% confidence interval 34.8 to 49.5)

Adverse Events Common Adverse Events: neutropenia, nausea, infections, fatigue, diarrhea
Serious Adverse Events: abdominal pain, vomiting, alanine aminotransferase (ALT) levels increased, anemia, constipation
Percentage that Discontinued due to Adverse Events: 7.5% (ribociclib); 2.1% (placebo)
Study Author Conclusions Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole. A higher rate of myelosuppression in the ribociclib group was reported.

The limitations of this trial are its sample size and the duration of monitoring.  The strength of this trial was the significant prolongation of progress-free survival with the addition of ribociclib to letrozole.  Although more adverse events correlated with ribociclib were apparent, there are appropriate management strategies available to minimize patient harm.  More studies and analysis on progression-free survival and adverse events are needed to properly define safety and efficacy of the medication in the long run.

References:

  1. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18(1):17.
  2. Breastcancer. Hormone receptor status. breastcancer.org. http://www.breastcancer.org/symptoms/diagnosis/hormone_status. Accessed October 18, 2016.
  3. Breastcancer. HER2 status. breastcancer.org. http://www.breastcancer.org/symptoms/diagnosis/her2. Accessed October 18, 2016.
  4. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016.

 

 

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