Volume 2 - Issue 1, November 2017

MONALEESA-2 supports the evolving role of CDK4/6 inhibitors in addition to standard therapy for postmenopausal women with HR-positive, HER2- negative advanced breast cancer Back


Endocrine therapy is standard-of-care in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, and is widely used to delay progression, prolong survival and maintain quality of life (QoL).1 However, acquired resistance occurs in the majority of patients, posing a major therapeutic challenge.2 A number of putative mechanisms have been proposed for the development of such resistance.2 The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of the CDK4 (INK4)-Retinoblastoma (Rb) pathway is commonly dysregulated in patients with breast cancer, and has been implicated in endocrine therapy resistance.3 Thus, CDK4/6 inhibitors such as ribociclib have been developed to target this pathway.3,4 A recently published, large systematic review by Beith et al1 described  the current treatment landscape for the somewhat difficult-to-treat group of women with hormone receptor-positive, HER2- breast cancer. Across 32 phase II and III studies, involving over 10,000 patients, the greatest improvement in median progression-free survival (PFS) was observed in the group who received a CDK4/6 inhibitor in addition to standard endocrine therapy.1 Herein, we recap previously published data from the randomised,placebo-controlled, phase III Mammary ONcology Assessment of LEE011’s (ribociclib’s) efficacy and SAafety (MONALEESA-2) trial, conducted in 29 countries.4 We also highlight the updated efficacy, safety and quality of life (QoL) data presented at the  recent 2017 American Society of Clinical Oncology (ASCO) Annual Meeting,  along with data from an Asian subgroup analysis presented at the 2016 European  Society for Medical Oncology (ESMO) Asia Congress.

MONALEESA-2 trial: Preliminary efficacy data

MONALEESA-24 evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib in combination with letrozole in postmenopausal women with  HR+, HER2-, recurrent or metastatic breast cancer who had received no prior systemic therapy for advanced disease. The study population included a high proportion of patients expected to be sensitive to endocrine therapy; 34% of patients in each treatment arm had de novo advanced/metastatic carcinoma, and approximately 60% had a prior disease-free interval of >24 months. A total of 668 patients were randomly assigned (exactly 1:1) to receive ribociclib (600 mg/day on a 3-weeks-on, one-week-off schedule) plus letrozole (2.5 mg/daycontinuously), or placebo plus letrozole. Ribociclib dose reductions only, in 200 mg increments, were allowed in cases of unacceptable toxicity. No treatment crossover was permitted.

In October 2016, the New England Journal of Medicine published convincing data from a pre-planned interim analysis of MONALEESA-2 data,4  conducted after a median of 15.3 months’ follow-up from randomisation. At data cut-off, 243 patients had experienced disease progression or died.

At this interim analysis, the study had met its primary endpoint, showing a 44% lower relative risk of disease progression with the addition of ribociclib to letrozole. Median PFS by local assessment was not reached (NR) (95% CI, 19.3 months to NR) in the ribociclib arm versus 14.7 months (95% CI, 13.0 to 16.5 months) in the placebo arm (hazard ratio [HR], 0.56; 95% CI, 0.43 to 0.72; P = 3.29 × 10-6 for superiority) (Figure 1). PFS rates at 12 months were 72.8% and 60.9%, respectively, and 18-month PFS rates were 63.0% and 42.2%, respectively. Blinded central review supported the significant improvement in PFS in ribociclib-treated patients age, race (Asian vs non-Asian), metastatic site, Eastern Co-operative Oncology Group (ECOG) performance status, prior therapy, and de novo versus existing metastatic disease.4 (HR, 0.59; 95% CI, 0.41 to 0.85; P = 0.002), and this benefit was observed across all predefined subgroups, including those defined  by age, race (Asian vs non-Asian), metastatic site, Eastern Co-operative Oncology Group (ECOG) performance status, prior therapy, and de novo  versus existing metastatic disease.4

Objective response rates (ORRs) and clinical benefit rates (CBRs) were also higher with the addition of ribociclib to letrozole (patients with measurable disease: ORRs, 52.7% vs 37.1%, respectively [P<0.001]; CBRs, 80.1% vs 71.8% [P=0.02]). Overall survival (OS) data were immature at the time of the interim analysis.4

The ribociclib + letrozole combination demonstrated an acceptable safety profile in most patients, with most non-haematologic toxicities of grade 1-2 severity. Grade 3-4 toxicities were largely manageable with dose reductions, allowing the majority of patients to remain on treatment; only 7.5% of patients discontinued the use of both agents due to adverse events (AEs). Dose reductions were necessary in 54% of patients in the ribociclib arm and 7% of those in the placebo arm; and median relative dose intensities were 100% for letrozole in both treatment arms, and 7.5% for ribociclib.4 A higher rate of myelosuppression was observed in ribociclib-treated patients, but haematologic AEs were consistent with that expected of CDK4/6 inhibitors combined with aromatase inhibitors. Neutropenia (74.3% vs 5.2% with ribociclib vs placebo) occurred mainly within the first month of treatment, and was reversible. Only 1.5% of ribociclib- treated patients experienced febrile neutropenia.4

MONALEESA-2 data updates: ASCO 2017

At the 2017 ASCO 53rd Annual Meeting held in Chicago, Illinois, in June, MONALEESA-2  trial investigators presented several posters highlighting updated efficacy, safety, and QoL data after an additional 11 months of follow-up (efficacy data cutoff, January 2, 2017).5-7 

Figure 1. Kaplan-Meier estimation of progression-free survival. Adapted from: Hortobagyi GN, et al. N Engl J Med. 2016;375:1738-1748.

Figure 2. Kaplan-Meier analysis of locally assessed progression-free survival. Adapted from: Hortobagyi GN, et al. ASCO 2017. Poster No. 1038.


After a median of 26 months’ follow-up, continued treatment benefit was demonstrated with the addition of ribociclib to letrozole. Updated efficacy results were reported in a poster by Hortobagyi et al5 during ASCO 2017.

Patients receiving ribociclib achieved a 9.3-month improvement in median PFS versus those receiving placebo (25.3 vs.16.0 months, respectively; HR, 0.568; 95% CI, 0.457–0.704; P=9.63 × 10–8) (Figure2); and central review confirmed this treatment benefit (HR, 0.564; 95% CI, 0.415–0.767; P=1.07×10-4). PFS rates at 24 months were 54.7% versus 35.9%, respectively. As with the interim analysis, strong ribociclib benefit was demonstrated consistently across all predefined patient subgroups (Figure 3).5

Figure 3. Subgroup analysis of locally assessed progression-free survival. Adapted from: Hortobagyi GN, et al. ASCO 2017. Poster No. 1038.

MONALEESA-2 data remain immature for OS analysis, after 15.0% and 19.8% of deaths in the ribociclib + letrozole and placebo + letrozole arms, respectively. However, the updated analysis suggested a trend toward longer survival with ribociclib added to letrozole; median OS durations were NR versus 33.0 months, respectively (HR, 0.746; 95% CI, 0.517–1.078; P=0.059)  (Figure 4). OS rates at 24
months were 86.7% in the ribociclib arm and 84.8% in the placebo arm.5 A further
OS analysis is planned when data reach maturity.

Analysis of best overall response showed ORRs of  54.5% with ribociclib +  
letrozole and 38.8% with placebo + letrozole among

Figure 4. Kaplan-Meier plot of locally assessed overall survival. Adapted from: Hortobagyi GN, et al. ASCO 2017. Poster No. 1038.

Figure 5. Adverse events observed in ≥15% of patients receiving ribociclib plus letrozole, by severity. Adapted from: Janni W, et al. ASCO 2017. Poster No. 1047.

patients with measurable disease, including complete/ partial response ratesof 4.3%/50.2% and 2.9/35.9%, respectively.CBRs were 80.2% and 71.8% in the ribociclib and placebo arms, respectively.5

Along with the overall safety data presented by Hortobagyi et al,5 a poster  by  Janni W, et al6 described in detail the most recent safety findings from MONALEESA-2.

The safety-evaluable population comprised 664 patients (ribociclib arm, n =334; placebo arm, n = 330).6 At a median follow-up of 15.3 months, the safety profile of ribociclib +letrozole was generally consistent with that reported in the interim analysis.4-6 Toxicity was manageable, with no new safety signals even in patients who had received ribociclib for >18 months.5, 6 The majority of AEs were of grade 1-2 severity.6 There was minimal impact of toxicity on the duration of combination treatment, and no evidence of cumulative toxicity.5

Table 1. Decreasing incidence of adverse events of special interest over long-term follow-up in patients receiving ribociclib + letrozole. Adapted from: Janni W, et al. ASCO 2017. Poster No. 1047.


AEs that were increased in frequency by >10% in the ribociclib arm versus the placebo arm were neutropenia, leukopenia, nausea, alopecia, anaemia, vomiting, diarrhoea, and increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST).6 AEs reported in at least 15% of patients in the ribociclib + letrozole arm are presented, by grade, in Figure 5.6.

The most frequent grade 3/4 AE among ribociclib-treated patients was neutropenia, reported in 59.3% of patients in the ribociclib + letrozole arm. The median time to onset of grade 3 neutropenia was 29 days, with a median time to resolution or normalisation of 15 days. Febrile neutropenia was infrequent, occurring in 1.5% of patients. Generally, the incidence and severity of neutropenia decreased over the course of treatment, with no new cases of grade 4 neutropenia reported after Cycle 9, suggesting a lack of cumulative bone marrow toxicity (Table 1).6 In addition, there were no significant increases in the frequency of predefined AEs of special interest with longer follow-up.4, 6

All AEs were reversible and manageable with dose interruptions or reductions.5 AEs led to dose interruptions in 68.0% vs 13.3% of patients in the ribociclib + letrozole vs placebo + letrozole arms, respectively; and dose reductions in 50.6% vs 4.2% of patients, respectively. The median time to first dose reduction in the ribociclib + letrozole arm was 86.8 days.6 AEs resulted in treatment discontinuations in 7.5% vs 2.1% of patients in the ribociclib + letrozole vs placebo + letrozole arms.

There were ten deaths reported within 30 days of the last study dose – seven (2.1%) in the ribociclib + letrozole arm and three (0.9%) in the placebo + letrozole arm. Causes of death were underlying breast cancer (n=2), acute respiratory failure (n=2), pneumonia (n=1), sudden death (n=1), and unknown cause (n=1) in the ribociclib + letrozole arm; and underlying breast cancer (n=2) and subdural haematoma (n=1) in the placebo + letrozole arm.5

Quality of life
Verma et al7 presented up-to-date QoL data from MONALEESA-2 at ASCO 2017. The European Organisation for Research and Treatment of Cancer’s cancer questionnaire (EORTC QLQ-C30) was used to explore patient-reported health-related quality of life (HRQoL), functioning, disease symptoms and treatment-related AEs in study participants.

The results suggested that the benefit of adding ribociclib to letrozole was not associated with a significant negative impact on overall HRQoL. There were no statistically significant or clinically meaningful differences between the arms with respect to key symptoms (including fatigue, nausea and vomiting) or other QoL domains including physical, role, cognitive, emotional and social functioning domains. There were also no significant or clinically meaningful differences in EORTC QLQ-BR23 domains such as side effects, future perspectives, and distress from alopecia.7

In addition, there was a clinically meaningful reduction in pain observed only in the ribociclib arm.7

MONALEESA-2 Asian subgroup analysis: ESMO 2016

In Asia, advanced breast cancer represents a significant health burden, with 24% of breast cancers worldwide diagnosed in the Asian region.8 Robust findings from the predefined MONALEESA-2 Asian subset analysis were presented at the ESMO Asia Congress in December 2016.9

For the purpose of the analysis, Asian patients were defined by geographic region and by race; a total of 68 patients were treated within Asian countries, and 51 patients self-reported as being of Asian race. Baseline characteristics of Asian- and non-Asian-region groups were largely comparable with those of the overall population.9

Figure 6. Kaplan-Meier estimates of progression-free survival (ribociclib + letrozole vs placebo + letrozole) by geographical region9. Adapted from: Yap YS, et al. ESMO Asia 2016. Abstract LBA1.

Figure 7. Overall response rate (ribociclib + letrozole vs placebo + letrozole) by geographical region9. Adapted from: Yap YS, et al. ESMO Asia 2016. Abstract LBA1.

Asian subgroup analysis: Efficacy
Efficacy outcomes were consistent with the overall trial results. Patients treated in the Asian region showed a significant 70% improvement in PFS with ribociclib + letrozole compared with letrozole alone (median: NR vs 11.0 months, respectively; HR, 0.298; 95% CI, 0.134–0.662); see Figure 6). In the non-Asian region, median PFS durations were NR vs 15.2 months, respectively (HR, 0.602; 95% CI,0.457–0.792). In patients identifying as being of Asian race, the concurrent use of ribociclib also significantly improved PFS by 61% versus letrozole alone (HR, 0.387 [95% CI, 0.166–0.906]).9

Response rates in the Asian subanalysis showed similar trends to the overall population. Among patients treated in the Asian region, ORRs were 60% in the ribociclib arm versus 24% in the placebo arm (Figure 7). This trend was more pronounced than that observed in the non-Asian region (39% vs 28%, respectively). There were similar trends in ORR when patients were evaluated by Asian versus non-Asian race.9

Asian subgroup analysis: Safety
The safety profile in patients treated in the Asian region was comparable with the overall study population. The most frequent AEs of any grade were neutropenia and nausea, both in Asian and non-Asian regions. The most common grade 3/4 AEs (≥5% of ribociclib-treated patients in the Asian region) were neutropenia (71% vs 0% with ribociclib vs placebo) and eukopenia (14% vs 0%, respectively). The safety profile was similar in patients evaluated by Asian race.9

Take-home messages

  • Acquired resistance to endocrine therapy poses a major therapeutic challenge in the treatment of HR+, HER2- advanced breast cancer.2 CDK4/6 inhibitors such as ribociclib have been developed in an attempt to overcome this resistance.3, 4
  • The ongoing, international MONALEESA-2 phase III trial continues to demonstrate robust long-term PFS benefit with the addition of ribociclib
    to first-line letrozole therapy in a population of postmenopausal women with HR+, HER2- disease.4, 5
  • The ribociclib + letrozole combination was well tolerated, but was associated with an increase in myelosuppression that was manageable with dose reductions and/or interruptions. 4, 6 Combination therapy did not adversely impact HRQoL in this population.7


The robust results of the phase III MONALEESA-2 trial show appreciable benefit from the addition of ribociclib to letrozole in the first-line recurrent or metastatic setting. While survival data remain immature, significant improvement in PFS and odds of response were demonstrated in ribociclib-treated patients, including among Asian and Asia-treated patients. Ribociclib use was also associated with improvement in cancer pain and no clinically meaningful impact on QoL. Although a higher rate of myelosuppression –described as a CDK 4/6 class effect – was evident with the combination, the safety profile was cceptable, reversible and manageable.4 Promising data such as those presented in MONALEESA-2 are contributing to a changing breast cancer treatment landscape, and it has been suggested that such data are likely to influence the future standard of care for postmenopausal women with HR+, HER2- advanced disease.1


  1. Beith J, Burslem K, Bell R, et al. Hormone receptor positive, HER2 negative metastatic breast cancer: A systematic review of the current treatment landscape. Asia Pac J Clin Oncol.2016;12 Suppl 1:3-18.
  2. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233-47.
  3. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer:CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med. 2014;7:203-15.
  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;375:1738-1748.
  5. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib + letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. ASCO 2017. Poster No. 1038.
  6. Janni W, Burris HA, Blackwell KL, et al. First-line ribociclib +letrozole for postmenopausal women with HR+, HER2– ABC:MONALEESA-2 safety results. ASCO 2017. Poster No. 1047.
  7. Verma S, O’Shaughnessy J, Burris HA, et al. Health-related quality of life of postmenopausal women with hormone receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: Results from MONALEESA-2. ASCO 2017. Poster No. 1020.
  8. Youlden DR, Cramb SM, Yip CH, Baade PD. Incidence and mortality of female breast cancer in the Asia-Pacific region. Cancer Biol Med. 2014;11:101-15.
  9. Yap YS, Tseng LM, Blackwell KL, et al. First-line ribociclib + letrozole in postmenopausal Asian women with HR+, HER2- advanced breast cancer: A subgroup analysis from MONALEESA-2. Abstract LBA1. ESMO Asia 2016.