When in Breast Cancer Treatment Are CDK4/6 Inhibitors Best?

Source: The study was led by Noor Wortelboer, MD, Netherlands Cancer Institute in Amsterdam, Netherlands. It was published online on February 19 in JAMA Oncology.

From: medscape.com

TOPLINE:

First-line cyclin-dependent kinase (CDK) 4 and 6 inhibitors (CDK4/6i) use did not improve overall survival compared with second-line use in hormone receptor-positive, ERBB2-negative advanced breast cancer, with median overall survival of 47.9 vs 48.1 months respectively. Post hoc analysis suggested potential benefit with first-line use in premenopausal patients.

METHODOLOGY:

• The phase III randomized SONIA trial was designed to directly address whether first-line CDK4/6i treatment meaningfully improves outcome beyond the established benefit in later lines.
• This trial enrolled 1050 patients with hormone receptor-positive, ERBB2-negative advanced breast cancer who had not received prior treatment for advanced disease, with a median age of 64 years.
• Participants were randomly assigned 1:1 to receive either aromatase inhibitor plus CDK4/6i as first-line treatment followed by fulvestrant (n = 524) or aromatase inhibitor followed by fulvestrant plus CDK4/6i as second-line treatment (n = 526).
• Analysis included a median follow-up of 58.5 months, with data cutoff on September 1, 2024, and overall survival as a key secondary endpoint.
• Research was conducted across 74 Dutch hospitals in compliance with the Declaration of Helsinki and International Guidelines for Good Clinical Practice.

TAKEAWAY:

• Median overall survival showed no significant difference between first-line CDK4/6i (47.9 months; 95% CI, 44.0-54.3) and second-line CDK4/6i groups (48.1 months; 95% CI, 44.7-52.0) with hazard ratio [HR], 0.91 (95% CI, 0.77-1.07; P = .24).
• Post hoc subgroup analysis revealed an overall survival benefit with first-line use in premenopausal patients (HR, 0.53; 95% CI, 0.32-0.87) but not in postmenopausal patients (HR, 1.00; 95% CI, 0.84-1.19; P for interaction = .01).
• First-line vs second-line CDK4/6i use was associated with more grade 3 or higher adverse events (3400 vs 2242 events).
• Among patients who discontinued second-line treatment, subsequent anticancer therapy patterns were similar between groups (84.8% in first-line group vs 84.2% in second-line group).

IN PRACTICE:

“[F]irst-line CDK4/6i use did not improve OS compared with second-line use but did increase treatment-related and financial toxic effects in [hormone receptor]-positive, ERBB2-negative ABC. Post hoc analysis suggests that the impact of CDK4/6i treatment sequencing may differ according to menopausal status, but these results should be interpreted with caution due to the inherent bias of post hoc analyses,” the authors of the study wrote.

“From a clinical point of view, these data suggest that a substantial percentage of patients with advanced, ER-positive breast cancer might be appropriately treated with endocrine therapy alone as initial treatment, reserving introduction of CDK4/6i for later in the course of the illness. This cohort would include postmenopausal patients with either endocrine-naive or minimally treated cancers and modest tumor burden, where there is a high expectation of endocrine sensitivity and a high likelihood of being capable of receiving treatment at crossover. Offering these individuals endocrine therapy alone with opportunity for CDK4/6i at crossover is likely to be a well-tolerated and effective option. Conversely, in patients with more extensive disease or prior endocrine therapy, tumors with PIK3CA variations, or premenopausal status, combination treatment with a CDK4/6i looks more valuable,” Carmine Valenza, MD, MPH, and Harold J. Burstein, MD, PhD, wrote in an accompanying editorial.