MONALEESA Analyses Show Widespread Benefit for Ribociclib in Hormone Receptor–Positive, HER2-Negative Breast Cancer

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Further analyses of the ­MONALEESA metastatic breast cancer trials have shown that the benefit of ribociclib plus endocrine therapy in the first-line setting extends to most intrinsic molecular subtypes and is consistent across multiple subgroups. The studies were presented at the 2021 San Antonio Breast Cancer Symposium.

A pooled analysis of MONALEESA-2, -3, and -7 data showed that patients with luminal A, luminal B, and HER2-enriched tumor subtypes had improved overall survival when treated with ribociclib plus endocrine therapy vs endocrine therapy alone, said Lisa A. Carey, MD, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research and Deputy Director of Clinical Sciences, University of North Carolina in Chapel Hill.1

Lisa A. Carey, MD

Lisa A. Carey, MD

Joyce O’Shaughnessy, MD

Joyce O’Shaughnessy, MD

Based on an exploratory subgroup analysis of MONALEESA-2, Joyce O’Shaughnessy, MD, reported that the overall survival benefit with the combination was consistent regardless of disease site, number of metastases, or receipt of prior therapy.2 Dr. O’Shaughnessy is the Celebrating Women Endowed Chair in Breast Cancer Research at Baylor University Medical Center and Chair of Breast Cancer Research at Texas Oncology and the US Oncology Network in Dallas.

The MONALEESA trials evaluated the addition of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib to endocrine therapy in postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer. MONALEESA-2 enrolled 668 participants, and the MONALEESA-2, -3 and -7 trials enrolled a total of 2,066 patients.

MONALEESA-2 Subgroup Analyses

As previously reported, the final overall analysis of ­MONALEESA-2 showed improved overall survival with ribociclib plus letrozole vs letrozole alone as first-line treatment (63.9 vs 51.4 months; hazard ratio [HR] = 0.76; P = .004).3 At 5 years, 52.3% of the combination arm was alive vs 43.9% of the control arm; this rate was 44.2% and 32.0%, respectively, at 6 years, Dr. O’Shaughnessy said.

“The median overall survival is the longest reported in any phase III clinical trial for advanced breast ­cancer, and the first to exceed 5 years,” Dr. O’Shaughnessy noted. 

The latest analysis, based on a median follow-up of 80 months, was exploratory and not powered for significance or adjusted for multiplicity. Benefits in overall survival in the prespecified subgroups were consistent with the previously reported intent-to-treat analysis, she reported in San Antonio.

“Independent of the metastatic site (bone, liver, or liver or lung), number of metastatic sites (< 3 or ≥ 3), or prior (neo)adjuvant chemotherapy or endocrine therapy, this exploratory subgroup analysis demonstrated improved survival with first-line ribociclib plus letrozole compared with placebo and letrozole. Consistent improvement in long-term survival at 5 and 6 years with ribociclib was observed in all subgroups,” Dr. O’Shaughnessy said.

Hazard ratios by prior treatment were:

  • Prior chemotherapy: HR = 0.74 (95% confidence interval [CI] = 0.56–0.98)
  • No prior chemotherapy: HR = 0.78 (95% CI = 0.59–1.03)
  • No prior endocrine therapy: HR = 0.70 (95% CI = 0.52–0.94)
  • Prior aromatase inhibitor: HR = 0.63 (95% CI = 0.32–1.24)
  • Tamoxifen, with or without an aromatase inhibitor: HR = 0.86 (95% CI = 0.64–1.15).

By metastatic burden or site, hazard ratios were:

  • With bone-alone metastases: HR = 0.78 (95% CI = 0.50–1.21)
  • Without bone-alone metastases: HR = 0.77 (95% CI = 0.61–0.96)
  • With less than three metastatic sites: HR = 0.78 (95% CI = 0.61–1.00)
  • With at least three metastatic sites: HR = 0.71 (95% CI = 0.51–0.98)
  • With liver metastases: HR = 0.81 (95% CI = 0.54–1.24)
  • Without liver metastases: HR = 0.77 (95% CI = 0.62–0.97)
  • With liver or lung metastases: HR = 0.81 (95% CI = 0.62–1.05)
  • Without liver or lung metastases: HR = 0.71 (95% CI = 0.53–0.96).

For the subgroup of patients with liver metastases, no real difference was observed between the treatment arms; however, there was a late separation of the survival curves. Overall survival at 5 and 6 years was 37.2% and 31.0%, respectively, for the ribociclib/endocrine therapy arm vs 28.4% and 18.9%, respectively, with endocrine therapy alone.  

Pooled Analysis Shows Benefit Across Most Intrinsic Subtypes

MONALEESA-2, -3, and -7 have demonstrated a consistent overall survival benefit with ribociclib, regardless of the endocrine therapy partner, line of therapy, or menopausal status. In San Antonio, Dr. Carey further confirmed benefit in three of four intrinsic subtypes of disease. 

The analysis by intrinsic subtype was based on 997 tumor samples from these three trials. Subtypes included luminal A (54%), luminal B (28%), HER2-enriched (15%), and basal-like (3%). Approximately 70% were from primary tumors in the pooled data set.

On the univariable analysis, the overall survival benefit achieved with ribociclib/endocrine therapy was observed for the three most common subtypes: luminal A (HR = 0.75; P = .021), luminal B (HR = 0.69; P = .023), and HER2-enriched (HR = 0.60; P = .018). Although the basal-like subgroup saw no benefit (HR = 1.89; P = .148), this subset of patients was too small to draw conclusions, she cautioned.

In the multivariable model, interaction test results between subtype and treatment arm were statistically significant after adjusting for clinical covariates (P = .0065). A consistent overall survival benefit was observed for the intent-to-treat population (HR = 0.76; P < .0001) and the biomarker population (HR = 0.75; P = .0012).

“Intrinsic subtype was prognostic for overall survival,” Dr. ­Carey further reported. “Overall survival was associated with subtype in both the ribociclib plus endocrine therapy and placebo plus endocrine therapy arms (P < .0001 for both).”

Median overall survival was longest for patients with luminal A tumors: 68.0 months in patients receiving the combination and 54.6 months in those receiving endocrine therapy alone. It was shortest in patients with basal-like tumors—19.4 months and 21.2 months, respectively—possibly because this subtype is not endocrine-sensitive, “and CDK4/6 inhibitors cannot salvage non–endocrine-sensitive tumors,” she proposed. The prognostic power held up in the multivariable model.

Focusing on HER2-Enriched Tumors 

Dr. Carey considered the benefit seen in patients with a HER2-enriched subtype to be particularly encouraging, considering that subtype has been associated with resistance to endocrine therapy and worse outcomes compared with luminal A and luminal B subtypes. The combination is being further investigated in the international phase III HARMONIA trial, which will test ribociclib head-to-head with palbociclib, in patients with the HER2-enriched subtype. HARMONIA is the first prospective phase III trial to enroll patients selected by RNA-based molecular subtyping of their tumors and the first to directly compare two CDK4/6 inhibitors.

“HARMONIA will examine whether ribociclib has a particular impact in HER2-enriched tumors based on these clinical data and preclinical data generated in patient-derived xenograft models,” she said.

“We are discovering there is lots of molecular heterogeneity within clinically ascertained groups of patients,” but how this changes the treatment strategy in the clinic remains unknown, Dr. Carey commented during the discussion period. “When do we move past clinical [determinations] and take the next step with molecular testing? It wouldn’t surprise me to find that we still end up with antiestrogen therapies as a key component…, but we already know that HER2-enriched tumors behave differently, and we may need to bring different treatment modalities to bear.” 

DISCLOSURE: Dr. Carey has received research funding (institutional) from Syndax, Novartis, NanoString Technologies, AbbVie, Seattle Genetics, and Veracyte; has an immediate family with a relationship with Falcon Therapeutics; and has uncompensated relationships with Sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, AstraZeneca/Daiichi Sankyo, Aptitude Health, Exact Sciences, and Eisai. Dr. O’Shaughnessy has received honoraria serving as a consultant or advisor to AbbVie, Agendia, Amgen Biotechnology, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, Genentech, Genomic Health, GRAIL, Immunomedics, Heron Therapeutics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Eli Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Prime Oncology, Roche, Seattle Genetics, Syndax Pharmaceuticals, and Takeda.


1. Carey LA, Solovieff N, Andre F, et al: Correlative analysis of overall survival by intrinsic subtype across MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2– advanced breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-00. Presented December 8, 2021.

2. O’Shaughnessy J, Stemmer SM, Burris HA, et al: Overall survival subgroup analysis by metastatic site from the phase 3 MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with HR+/HER2– advanced breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-01. Presented December 8, 2021.

3. Hortobagyi GN, Stemmer SM, Burris III HA, et al: Overall survival results from the phase III MONALEESA-2 trial of postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative advanced breast cancer treated with endocrine therapy ± ribociclib. ESMO Congress 2021. Abstract LBA17_PR. Presented September 19, 2021.


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