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SAN ANTONIO - Two analyses of first-line ribociclib (Kisqali) trials showed that the CDK4/6 inhibitor's survival benefit in advanced, hormone receptor (HR)-positive/HER2-negative breast cancer was independent of metastatic burden or site, and extended to certain intrinsic subtypes as well.

The first study, an exploratory subgroup analysis of the MONALEESA-2 trial, showed a consistent overall survival (OS) benefit for postmenopausal women who received ribociclib in addition to letrozole regardless of the site or number of metastases, and regardless of their prior therapy, reported Joyce O'Shaughnessy, MD, of Baylor University Medical Center in Dallas.

Similarly, an analysis of three MONALEESA trials demonstrated that patients with luminal A, luminal B, and HER2-enriched tumor subtypes had improved OS when treated with ribociclib plus endocrine therapy versus endocrine therapy alone, according to Lisa A. Carey, MD, of the University of North Carolina in Chapel Hill.

Both studies were presented at the San Antonio Breast Cancer Symposium.

Subgroup Analysis of MONALEESA-2

Previously published results from the phase III MONALEESA-2 trial showed improved OS for patients receiving ribociclib plus letrozole versus letrozole alone as first-line treatment for advanced HR-positive/HER2-negative breast cancer (63.9 vs 51.4 months; HR 0.76, 95% CI 0.63-0.93, P=0.004).

In the new analysis (with a median follow-up of 80 months), O'Shaughnessy presented data showing a "consistent" OS benefit with ribociclib across prespecified subgroups based on prior treatment:

• Prior chemotherapy: HR 0.74 (95% CI 0.56-0.98)
• No prior chemotherapy: HR 0.78 (95% 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)

And by metastatic burden or site:

• With bone-only metastases: HR 0.78 (95% CI 0.50-1.21)
• Without bone-only metastases: HR 0.77 (95% CI 0.61-0.96)
• <3 metastatic sites: HR 0.78 (95% CI 0.61-1.00)
• ≥3 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)

Among patients with liver metastases, the investigators saw no difference in median OS between groups, but there was a late separation of the survival curves, with 5- and 6-year OS rates of 37.2% and 31.0%, respectively, for the ribociclib-treated patients versus 28.4% and 18.9% for the placebo patients. Similarly, this pattern was seen in patients with or without liver or lung metastases.

"With this presentation, we can now confirm that with overall survival -- as has been shown with progression-free survival -- the relative ribociclib benefit is consistent [across all anatomically-defined subgroups], and that anatomic factors retain prognostic significance," commented David Cescon, MD, PhD, of Princess Margaret Cancer Centre in Toronto, who served as a discussant for the two studies.

For example, the median OS in ribociclib-treated patients was highest among those with bone-only metastases (72.6 months), those without lung or liver lesions (70.5 months), and those with less than three metastatic sites (68 months), while lowest among those with liver lesions (37.7 months), those with liver or lung lesions (55.5 months), and those with three or more lesions (55.5 months).

"This highlights the fact that absolute overall survival of ribociclib does vary by patient population and that, perhaps, it is the patients with the more indolent metastatic disease who gain the largest absolute benefit in overall survival," added Cescon.

Ribociclib Benefit Seen Across Most Intrinsic Subtypes

The OS analysis by intrinsic subtype was based on 997 tumor samples from the MONALEESA-2, -3, and -7 trials. Luminal A was the most common subtype (54%), followed by luminal B (28%), HER2-enriched (15%), and basal-like (3%).

Carey reported that intrinsic subtype was prognostic, with median OS longest in luminal A tumors (68.0 months with ribociclib plus endocrine therapy vs 54.6 months with endocrine therapy alone) and shortest in patients with basal-like tumors (19.4 months with ribociclib and 21.2 months without).

On univariable analysis, the OS benefit with ribociclib was observed for the three most common subtypes:

• Luminal A: HR 0.75, P=0.021
• Luminal B: HR 0.69, P=0.023
• HER2-enriched: HR 0.50, P=0.018

While patients with the basal-like subtype did not see an OS benefit with ribociclib (HR 1.80, P=0.148), Carey cautioned that the sample size makes those results difficult to interpret.

She noted that the benefit demonstrated in HER2-enriched subtype patients is particularly encouraging considering that subtype has been associated with resistance to endocrine therapy and poorer outcomes compared with luminal A and luminal B. This is being further investigated in the HARMONIA phase III trial, which will test ribociclib head-to-head with another CDK4/6 inhibitor, palbociclib (Ibrance), in patients with the HER2-enriched subtype.

Cescon suggested it's possible ribociclib has an advantage in certain intrinsic subtypes, as is being investigated in HARMONIA.