The addition of the CDK4/6 inhibitor palbociclib to anti-HER2 and endocrine therapy (ET) significantly improves progression-free survival (PFS) in patients with hormone receptor-positive, HER-positive (HR+, HER+) metastatic breast cancer (mBC) in the first-line setting, according to the results of the phase III AFT-38 PATINA trial.

“There is a strong scientific rationale for blocking CDK4/6 in HER2+ disease … Our results reinforce this rationale for overcoming resistance to anti-HER2 therapy and ET by adding CDK4/6 inhibition,” said Dr Otto Metzger from the Dana-Farber Cancer Institute, Boston, Massachusetts, US, at SABCS 2024.

In terms of the primary endpoint of investigator-assessed PFS, anti-HER2 and ET fared better with the addition of palbociclib as opposed to without after a median follow-up of 52.6 months (median 44.3 vs 29.1 months; hazard ratio [HR], 0.74; p_one-sided=0.0074). [SABCS 2024, abstract GS2-12]

“There was an early separation of the [Kaplan-Meier] curves that continued over time. By month 60, we saw an absolute improvement close to 10 percent in the palbociclib arm (43.2 percent vs 33.4 percent),” Metzger said.

The magnitude of benefit was maintained when looking at the PFS by stratification subgroups, with HRs ranging between 0.68 and 0.76.

The palbociclib arm performed better than the control arm in terms of confirmed objective response (29.2 percent vs 22.2 percent; p=0.046) and clinical benefit rates (89.3 percent vs 81.3 percent; p=0.01).

At the time of the analysis, median overall survival (OS) was not evaluable (NE) in the palbociclib arm vs 77 months in the control arm. Five-year OS estimates were 74.3 percent vs 69.8 percent in the respective palbociclib and control arms (HR, 0.86).

Grade ≥4 adverse event (AE) rates were similar between the palbociclib and control arms (12.3 percent vs 8.9 percent; p=0.21). In the palbociclib arm, grade 3 neutropenia was the most frequent AE (63.2 percent), and treatment discontinuation rate due to AEs was 7.5 percent. There were no treatment-related deaths reported in either arm.

Over a year of improvement

“Anti-HER2 therapies have significantly improved survival outcomes in HER2? BC, but resistance to therapy remains inevitable for the majority of patients with advanced disease,” Metzger said. Based on preclinical evidence that CDK4/6 inhibition could prevent resistance to both ET and anti-HER2 therapy, the team set out to evaluate the addition of palbociclib to anti-HER2 and ET for HR+, HER2+ mBC.

A total of 518 patients (median age 53.4 years, 99.4 percent women) with HR+, HER2+ mBC who had no prior treatment in the advanced setting beyond induction were randomized 1:1 to receive anti-HER2 therapy (trastuzumab ± pertuzumab) and ET with palbociclib 125 mg QD (days 1?21) or without.

Almost all participants (97.3 percent) received pertuzumab. Ninety-one percent received an aromatase inhibitor as ET, while the rest received fulvestrant. Overall, participants received a median of six induction treatment cycles. Prior to randomization, over two-thirds of participants had complete or partial response with induction therapy.

“[Our] study demonstrates a clinically meaningful PFS improvement among patients with HR+, HER2+ mBC,” Metzger said. “The median PFS in the control arm … far exceeds what we had expected, and in spite of that, we saw a 15.2-month improvement ? which translates to over a year of improvement ? with the addition of palbociclib.”

Moving away from a ‘one-size-fits-all approach’

“The PFS data are impressive,” noted discussant Dr Sara Hurvitz from the University of Washington School of Medicine, Seattle, Washington, US. “The 29.1-month [median PFS] in the control arm is quite high, [while that] in the palbociclib arm is incredible and, I would argue, historic.”

She underscored that it might be time to move away from a ‘one-size-fits-all’ approach to HER2+ BC, as the study provided “definitive proof that there are benefits to targeting more than just HER2 in HER2+ BC. CDK 4/6 inhibitors should be considered part of the armamentarium for HR+, HER2+ disease.”

However, Hurvitz stressed that nuanced patient selection is warranted, as well as patient-reported outcomes and more biomarker work. “There is strong rationale to test additional targeted therapies in HER2+ BC and design smart clinical trials to find and identify the right treatment for the right patient.”