Palbociclib Plus Anti-HER2 and Endocrine Therapy Prolongs PFS in HR+/HER2+ Breast Cancer

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The addition of palbociclib plus standard-of-care (SOC) anti-HER2 and endocrine therapy in the first-line maintenance setting produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs SOC alone in patients with hormone receptor (HR)–positive, HER2-positive metastatic breast cancer, according to findings from the phase 3 AFT-38 PATINA trial (NCT02947685) presented at the 2024 San Antonio Breast Cancer Symposium.¹

Our results really reinforce the strong scientific rationale for overcoming resistance to anti-HER2 therapy and endocrine therapy with the addition of palbociclib,” Otto Metzger, MD, of Dana-Farber Cancer Institute, during his presentation.

Palbociclib plus anti-HER2 therapy and endocrine therapy had median PFS of 44.3 months (95% CI, 32.4-60.9) vs 29.1 months (95% CI, 23.3-38.6) with only anti-HER2 and endocrine therapy (HR, 0.74; 95% CI, 0.58-0.94; unstratified 1-sided P = .0074). There was a median follow-up of 52.6 months in patients who are alive and disease free.

Previously, anti-HER2 therapies have significantly improved survival in patients with breast cancer, and about 15% to 20% of breast cancer overexpress HER2. Palbociclib is a CDK4/6 inhibitor previously approved for adult patients with hormone receptor­–positive, HER2-negative metastatic breast cancer with an aromatase inhibitor or with fulvestrant depending on the line of therapy.

“There is a strong rationale for blocking CDK4/6 in HER2-positive disease,” Metzger explained. “The cyclin D1-CDK4 axis is essential for initiation and maintenance of growth in HER2-positive disease. The same axis drives resistance to the HER2 pathway blockade. This combined CDK4/6 and HER2 inhibition has shown to be synergistic and have a profound antitumor activity in preclinical models.”

The investigators of the open-label, phase 3 AFT-38 PATINA trial (NCT02947685) randomly assigned 518 patients 1:1 to 125 mg of oral palbociclib daily plus anti-HER2 therapy of trastuzumab (Herceptin) or trastuzumab plus pertuzumab (Perjeta) every 3 weeks plus endocrine therapy of letrozole, anastrozole, exemestane, or fulvestrant (n = 261) vs the combination without palbociclib (n = 257) until progressive disease or toxicity. Patients had to complete induction chemotherapy and have no evidence of disease progression prior to enrollment.

To assess these combinations as frontline maintenance therapy, the primary end point was investigator-assessed PFS, and secondary end points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety. Patients were enrolled from June 2017 to July 2021, and the final data cutoff for PFS analysis was October 15, 2024.

Along with the improved PFS for patients overall, the investigators also observed the HR favored patients in the subgroup analysis of PFS. In patients who received prior anti-HER2 therapy, the HR was 0.76 (95% CI, 0.57-1.01); in those with no prior anti-HER2 treatment, 0.68 (95% CI, 0.543-1.07); in those with best response to induction of complete response or partial response, 0.76 (95% CI, 0.57-1.02); and in those with best response to induction of stable disease, 0.72 (0.47-1.12).

The confirmed ORR by investigator assessment was 29.9% with palbociclib compared with 22.2% in the control arm (P = .046). Similarly, the CBR was also slightly higher with palbociclib at 89.3% vs 81.3%, respectively (P = .01).

An interim analysis of the OS in the PATINA trial showed the median OS was not evaluable (NE) in patients receiving the palbociclib combination (95% CI, 71.6-NE) vs 77 months (95% CI, 72-NE) with the anti-HER2 therapy and endocrine therapy alone (HR, 0.86; 95% CI, 0.60-1.24). The 3-year OS rates were 87.0% (95% CI, 82.8%-91.2%) compared with 84.7% (95% CI, 80.0%-89.3%) with the experimental and control arms, respectively; the 5-year OS rates were 74.3% (95% CI, 67.7%-80.9%) and 69.8% (95% CI, 62.4%-77.2%).

Investigators reported on adverse events (AEs) of grade 2 or higher in 10% or more of patients on the trial, showing that neutropenia was the most common AE. Neutropenia was the most common AE overall, which Metzger noted was consistent with the toxicity profile of palbociclib. In the experimental group, the rate of grade 2 neutropenia was 19.9%, grade 3 was 63.2%, and grade 4 was 4.6%; in the control group, grade 2 was 4.0%, grade 3 was 4.4%, and grade 4 was 0%.

Otherwise, common AEs in the palbociclib arm included white blood cell count decreased, diarrhea, stomatitis, and fatigue, but only white blood cell count decreased had a grade 4 event (0.4%). In the control arm, the other most common events were arthralgia, diarrhea, and fatigue.

Additionally, grade 4 or higher AEs were similar across study arms at 12.3% with the palbociclib regimen vs 8.9% in the group not given palbociclib (P = .21), but there were no grade 5 AEs. Treatment discontinuation because of AEs was seen in 7.5% of patients receiving palbociclib.

Overall, the median age in the trial was 53.4 years old (IQR, 44.2-61.4), and the majority of the patients were white (91.7%) and female (99.4%). The median number of induction cycles was 6 (range, 4-8). Almost all patients had previously received pertuzumab (97.3%) and received an aromatase inhibitor as endocrine therapy (90.9%), while the rest received fulvestrant (9.1%). There were 71.8% of patients who received prior anti-HER2 therapy in the neoadjuvant or adjuvant setting, and 68.5% had a complete or partial response to induction therapy.

“The PATINA phase 3 study demonstrated a clinically meaningful improvement in PFS among patients diagnosed with hormone receptor–positive, HER2-positive disease. The median PFS in the control arm of our study is 29.1 months. This far exceeds what we had expected, and in spite of that, we're seeing a 15.2-month improvement—it's more than a year of improvement with the addition of palbociclib,” Metzger said. “The toxicity was manageable, and I would argue that palbociclib, when added to anti-HER2 and endocrine therapy, may represent a new standard of care for patients diagnosed with hormone receptor–positive, HER2-positive breast cancer.”

_Reference

Metzger O, Mandrekar S, DeMichele A, et al. AFT-38 PATINA: a randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib plus trastuzumab (Enhertu) or trastuzumab plus pertuzumab (Perjeta) + endocrine therapy vs. anti-HER2 Therapy + endocrine therapy after induction treatment for hormone receptor-positive (HR+)/HER-positive metastatic breast cancer. Presented at: San Antonio Breast Cancer Conference; December 10-13, 2024; San Antonio, TX. GS2-12.