SABCS 2021

The second day of the San Antonio Breast Cancer Symposium (SABCS) 2021 started with two talks focusing on the overall survival (OS) analyses from the phase III MONALEESA-2, MONALEESA-3 and MONALEESA-7 trials. The MONALEESA clinical trial programme has been investigating the efficacy and safety profiles of ribociclib + endocrine therapy (ET) versus placebo + ET across a diverse population of patients.¹

The first talk was given by Dr Lisa Carey from the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, US. The results presented focused on the exploratory analysis of OS by intrinsic subtype in postmenopausal patients with HR+/HER2- advanced breast cancer (aBC) across the MONALEESA-2, -3, and -7 trials.

Ribociclib + ET had previously demonstrated statistically significant progression-free survival (PFS) and OS benefit compared with placebo + ET.^2-7 A pooled analysis of MONALEESA trials had shown a significant improvement in PFS with ribociclib + ET versus placebo + ET in the luminal A (HR: 0.63, p=0.0007), luminal B (HR: 0.52, p<0.0001) and HER2-enriched (HR: 0.39, p<0.0001) subtypes of aBC.⁸

The analysis presented by Dr Carey evaluated the association of intrinsic subtype with OS using tumour samples from MONALEESA-2, -3 and -7. There were 997 samples in the analysis, of which 585 were from patients receiving ribociclib + ET and 412 were from patients receiving placebo + ET, and 71% were from primary tumours. The subtype distribution was 54.4% for luminal A, 27.9% for luminal B, 14.7% for HER2-enriched and 3.0% for basal-like aBC.

Ribociclib + ET showed an OS benefit in both the intention-to-treat (ITT) population (n=2,066, HR: 0.76, 95% CI: 0.67-0.86) and in the biomarker population (n=997, HR: 0.75, 95% CI; 0.63-0.89) compared with placebo + ET.

"Intrinsic subtype was prognostic in this dataset" remarked Dr Carey, referring to the placebo + ET arm, "the luminal A had the longest median OS at just under 55 months. That was followed by luminal B that was about 10 months shorter. HER2-enriched: substantially shortened at 29 months, and the basal-like had the worst OS at 21 months." In the ribociclib + ET arm, this trend continued with median OS of 68, 58.8, 40.3 and 19.4 months in the luminal A, luminal B, HER2-enriched and basal-like subtype groups, respectively (p<0.0001 in both study arms). The subtypes remained prognostic in multivariable models (p<0.001 in both study arms).

In a univariable analysis, the OS benefit with ribociclib + ET versus placebo + ET was consistent in the luminal A (p=0.021), luminal B (p=0.023) and HER2-enriched (p=0.018) subtypes, but not in the basal-like subtype. In multivariable analyses, the hazard ratios for OS benefit were 0.77 (95% CI: 0.60-0.99) for luminal A, 0.63 for luminal B (95% CI: 0.46-0.88) and 0.53 for HER2-enriched (95% CI: 0.35-0.80) subtypes.

In summary, the OS benefit observed with ribociclib + ET versus placebo + ET was consistent in the luminal A, luminal B and HER2-enriched subtypes. Patients with basal-like subtype did not benefit from ribociclib but "these results should be interpreted with caution due to the small sample sizes in this subgroup" cautioned Dr Carey. She also told the audience that the activity of ribociclib in the HER2-enriched subtype compared with the luminal subtypes, is being further investigated in the phase III HARMONIA trial.

The second talk was given by Dr Joyce O’Shaughnessy from Texas Oncology-Baylor Charles A Sammons Cancer Center, Dallas, TX, US. Dr O’Shaughnessy described the overall subgroup analysis results from MONALEESA-2 by metastatic site.

The OS benefit with ribociclib + letrozole (LET) versus placebo + LET in the MONALEESA-2 trial was reported at the ESMO 2021 Congress back in September (63.9 versus 51.4 months, HR: 0.76, 95% CI: 0.63-0.93, p=0.004).³ "The median overall survival in the ribociclib arm is the longest reported in any phase III clinical trial for advanced breast cancer and the first to exceed 5 years," emphasised Dr O'Shaughnessy.

In this session, she presented the exploratory OS analysis from MONALEESA-2 by location of metastases, number of metastatic sites and prior therapy. MONALEESA-2 included 668 patients who were randomised 1:1 to receive ribociclib + LET (n=334) or placebo + LET (n=334), who had not received prior chemotherapy or ET for advanced disease. The prespecified groups and the median OS in these groups were as follows:

• Bone-only metastases: 72.6 months with ribociclib + LET vs 56.4 months with placebo + LET (HR: 0.78, 95% CI: 0.50-1.21). OS benefit in patients without bone-only metastases was consistent with that of the ITT population
• Liver metastases: 37.7 months with ribociclib + LET vs 38.1 months with placebo + LET where a late separation in OS benefit was observed (HR: 0.81, 95% CI: 0.54-1.24):
  • At 5 years, OS rates were 37.2% in the ribociclib + LET arm and 28.4% in the placebo + LET arm
  • At 6 years the OS rates were 31.0% and 18.9%, respectively
• Lung metastases: 55.5 months with ribociclib + LET vs 51.4 months with placebo + LET where a late separation in OS benefit was observed (HR: 0.81, 95% CI: 0.62-1.05):
  • At 5 years, OS rates were 48.2% in the ribociclib + LET arm and 45.4% in the placebo + LET arm
  • At 6 years the rates were 40.5% and 31.2%, respectively
• <3 metastatic sites: 68.0 months with ribociclib + LET vs 56.1 months with placebo + LET (HR: 0.78, 95% CI: 0.61-1.00)
• ≥3 metastatic sites: 55.5 months with ribociclib + LET vs 46.5 months with placebo + LET (HR: 0.71, 95% CI: 0.51-0.98)
• Prior neoadjuvant chemotherapy: 52.0 months with ribociclib + LET vs 44.7 months with placebo + LET (HR: 0.74, 95% CI: 0.56-0.98)
• No prior neoadjuvant chemotherapy: 69.5 months with ribociclib + LET vs 58.5 months with placebo + LET (HR: 0.78, 95% CI: 0.59-1.03)
• OS benefit in patients who had or had not received prior neoadjuvant therapy was consistent with that in the ITT population³

In conclusion, ribociclib + LET demonstrated an OS benefit versus placebo + LET independent of metastatic site, number of metastatic sites and prior neoadjuvant chemotherapy or endocrine therapy in postmenopausal women with HR+/ HER2- aBC. A consistent improvement in long-term survival was observed at 5 and 6 years.

Overall, MONALEESA-2, -3 and -7 demonstrated a consistent OS benefit with ribociclib regardless of ET partner, line of therapy or menopausal status.^5,7

CI: confidence interval; ESMO: European Society for Medical Oncology; HER2: human epidermal growth factor receptor 2; HR+: hormone receptor-positive; HR: hazard ratio; MONALEESA: Mammary Oncology Assessment of LEE011’s Efficacy and Safety