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ESMO Breast Cancer Symposium Data Support First-Line CDK4/6 Inhibitor Combinations


NEW YORK – Data presented during the European Society of Medical Oncology Breast Cancer Symposium on Wednesday support the first-line benefit of CDK4/6 inhibitors plus hormone therapy for hormone receptor (HR)-positive, HER2-negative advanced breast cancer patients.

Researchers presented updated Phase III overall survival results at the meeting, showing a benefit with Novartis' CDK4/6 inhibitor Kisqali (ribociclib) plus hormone therapy in the first-line treatment setting as well as large-scale real-world data supporting the use of Pfizer's CDK4/6 inhibitor Ibrance (palbociclib) in the same indication.

Novartis' Phase III MONALEESA-3 trial pitted Kisqali plus fulvestrant against fulvestrant alone in postmenopausal, HR-positive, HER2-negative advanced breast cancer patients, both as a first and second-line treatment.

For several years now, the field has been aware of the confirmed overall survival benefit of adding Kisqali to hormone therapy; in early 2020, the New England Journal of Medicine published overall survival results after a median follow-up of 39.4 months, showing a significant benefit with Kisqali, which was consistent across treatment lines. While researchers did previously consider patients' outcomes based on their prior treatment status in this study, the median overall survival was not yet reached for the subset of patients who received the Kisqali combination in the first-line setting.

"So the investigators did ask Novartis to analyze the updated follow-up at 70.8 months [according to treatment line]," Patrick Neven, a professor in the gynecologic oncology department at the University Hospitals in Leuven, Belgium, said during a presentation Wednesday morning.

After 70.8 months of follow-up — for which the data cutoff was this past January — "we have an impressive benefit in the median overall survival," Neven said. In the first-line Kisqali-fulvestrant arm, the median overall survival was 67.4 months versus 51.8 months in the placebo-fulvestrant arm. As Neven pointed out, this translates to 1 out of 7 patients still living five years after the study treatment began.

Neven also shared data on two other MONALEESA-3 endpoints — progression-free survival and time to chemotherapy — which both improved with the Kisqali regimen. "Patients always want to know, 'How long will it take until I have to have chemotherapy,'" Neven said. Calling this "chemotherapy-free survival," or the time from randomization to the first line of chemotherapy or death, he pointed out a significant difference of 49.2 months versus 29.0 months in the Kisqali arm versus the placebo arm.

The safety profile of the treatment remained more or less in line with the earlier data presented from the MONALEESA-3.

"Ribociclib combined with fulvestrant demonstrated the longest median overall survival observed for a first-line population in a Phase III trial setting in advanced breast cancer as of today," Neven concluded, adding that the overall survival benefit was also continued in the second-line treatment setting during this follow-up analysis, even though this presentation focused on first-line treatment.

In a discussion of the data following Neven's presentation, Mafalda Oliveira, a medical oncologist at the Vall d'Hebron University Hospital in Barcelona, raised an eyebrow over the fact that a little over a third of the patients treated on the placebo arm went on to receive a CDK4/6 inhibitor after disease progression. "Perhaps this may not reflect the current treatment landscape in this context," she said. If more patients had switched to a CDK4/6 inhibitor-based regimen in the trial, as is likely to happen in the real world as Oliveira alluded to, the overall survival impact may have been more muted.

Even so, Oliveira agreed with the study authors that "these are impressive results."

Looking ahead, she pointed out that the overall survival results from the Phase III PALOMA-2 trial of Pfizer's CDK4/6 inhibitor Ibrance plus the aromatase inhibitor letrozole versus letrozole alone in treatment-naïve, HR-positive, HER2-negative breast cancer is set to be presented next month during the American Society of Clinical Oncology's annual meeting.

The field will also be interested in the overall survival results from the Phase III MONARCH-3 trial of Eli Lilly's CDK4/6 inhibitor Verzenio (abemaciclib) plus aromatase inhibitors versus aromatase inhibitors alone in this patient population, she added. Regulators approved the agent based on progression-free survival data, and the overall survival analysis is pending. Since data from these competing agents is forthcoming, Novartis can, for now, claim Kisqali is the only drug in its class to show overall survival benefit in this treatment setting.

The US Food and Drug Administration has approved all three of these CDK4/6 inhibitors with hormone therapy or aromatase inhibitors as initial treatment for HR-positive, HER2-negative, postmenopausal advanced breast cancer patients. The market availability of these drugs, however, has enabled real-world overall survival analyses while the field awaits randomized, Phase III trial readouts.

For example, Pfizer presented a poster during this same meeting, highlighting positive real-world evidence for its Ibrance combination in this first-line setting. Between February 2015 and March 2022, among 2,888 patients in Flatiron Health's repository of real-world data who began initial treatment with either Ibrance and an aromatase inhibitor or just an aromatase inhibitor, the median overall survival for patients treated with Ibrance was 49.1 months versus 43.2 months among those on just aromatase inhibitors. The findings represent a 24 percent reduction in the risk of death with Ibrance treatment and a 30 percent reduction in the risk of disease progression.

"This largest to date real-world comparative effectiveness study demonstrated that palbociclib plus aromatase inhibitors was significantly associated with prolonged overall survival versus aromatase inhibitor alone, supporting first-line palbociclib plus aromatase inhibitors as a standard of care for HR-positive, HER2-negative metastatic breast cancer patients," wrote the authors of that study, which included Hope Rugo, the director of breast oncology and clinical trials education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

Real-world retrospective analyses do not control for biases in the same way randomized clinical trials do, and even cross-trial comparisons are imperfect, making it difficult to determine the best CDK4/6 inhibitor combination for this breast cancer population. A head-to-head trial comparing Kisqali to Ibrance or Verzenio would be needed to make definitive judgments.

Meanwhile, these competing drugmakers are also working to move their agents into additional treatment lines. Novartis, for instance, is conducting the Phase III NATALEE trial evaluating Kisqali plus endocrine therapy as an adjuvant treatment for HR-positive, HER2-negative early-stage breast cancer — a market worth $7 billion by 2027. During a call to discuss its Q1 2022 financials last week, Novartis CEO Vas Narasimhan said that the firm expects a data readout from NATALEE in 2023.

In this same adjuvant setting, Eli Lilly's CDK4/6 inhibitor is already FDA approved as of October, although the indication specifies patients must have node-positive disease and a high risk of recurrence based on a certain Ki-67 score, which is a marker of cellular proliferation.

Interestingly, Pfizer's Ibrance did not add benefit in the adjuvant setting in the Phase III PALLAS trial, which was discontinued early.