Addition of the CDK4/6 inhibitor palbociclib to the current standard of care for first-line maintenance therapy after induction chemotherapy achieved statistically significant and clinically meaningful improvements in progression-free survival in patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer, according to late-breaking results from the phase III AFT-38 PATINA trial presented at the 2024 San Antonio Breast Cancer Symposium.1
Median progression-free survival was 44 months for patients who received palbociclib plus anti-HER2 therapy with the monoclonal antibody trastuzumab or trastuzumab plus pertuzumab and endocrine therapy vs 29 months in patients treated with anti-HER2 therapy plus endocrine therapy alone (P = .0074). Palbociclib extended median progression-free survival by more than 15 months, potentially extending the use of this CDK4/6 inhibitor to patients with HR-positive, HER2-positive metastatic breast cancer.
Palbociclib is currently approved in the United States for the treatment of adults with HR-positive, HER2-negative metastatic breast cancer as initial therapy combined with an aromatase inhibitor in postmenopausal women or with fulvestrant in patients who experienced disease progression after endocrine therapy.
Otto Metzger, MD
“PATINA is the first phase III trial to show that the addition of the CDK4/6 inhibitor palbociclib was of benefit as first-line maintenance therapy in HR-positive, HER2-positive metastatic breast cancer in combination with anti-HER2 and endocrine therapy,” said Otto Metzger, MD, study principal investigator. “These results suggest that palbociclib overcomes resistance to anti-HER2 therapy and endocrine therapy. The data support the potential of this maintenance treatment to slow disease progression and improve clinical outcomes in this patient population. This may represent a new standard of care for patients diagnosed with HR-positive, HER2-positive metastatic breast cancer.” Dr. Metzger is Assistant Professor of Medicine at Harvard Medical School and a medical oncologist at the Dana-Farber Cancer Institute, Boston.
HR-positive, HER2-positive breast cancer accounts for about 10% of all breast cancers. Most patients who are treated with the standard of care will develop resistance to anti-HER2 therapy and endocrine therapy, and there is a need for novel therapeutic approaches for this subtype.
Study Details
The randomized, open-label, international, phase III PATINA trial was sponsored by the Alliance Foundation Trials, in collaboration with six international cancer research groups in the United States, Germany, Italy, Spain, Australia, and New Zealand. Patients were enrolled with histologically confirmed HR-positive, HER2-positive metastatic breast cancer and no prior therapy in the advanced setting; they received six to eight cycles of induction chemotherapy with anti-HER2-therapy and chemotherapy. If there was no evidence of disease progression, they were randomly assigned to receive anti-HER2 therapy and endocrine therapy plus palbociclib (n = 261) or anti-HER2-therapy and endocrine therapy alone (n = 257). Options for endocrine therapy included aromatase inhibitors or fulvestrant; ovarian suppression was required for premenopausal patients.
Stratification factors were pertuzumab use (yes or no); prior anti-HER2 therapy in the (neo)adjuvant setting (yes or no); response to induction therapy (complete response or partial response vs stable disease); and type of endocrine therapy (fulvestrant or aromatase inhibitor). Median patient age was 53, and the majority were White. Nearly all patients (97%) received pertuzumab; about 28.2% received prior anti-HER2 therapy; 90% received an aromatase inhibitor; and 68.5% achieved a complete or partial response as best response to induction treatment prior to randomization.
Data cutoff for this analysis was October 2024. A total of 97.3% of patients received dual anti-HER2 therapy, and 90.9% received an aromatase inhibitor. The final analysis of the primary endpoint—investigator-assessed progression-free survival—was performed at a median follow-up of 53 months.
Key Results
The addition of palbociclib significantly improved progression-free survival by 26% compared with the control arm. Median progression-free survival was 44 months in the palbociclib arm compared with 29 months in the control arm. Palbociclib performed better in all stratification groups.
Confirmed objective response rate was 29.2% in the palbociclib arm compared with 22.2% in the control arm, respectively (P = .046). The clinical benefit rate was 89.3% in the palbociclib arm vs 81.3% in controls.
The most frequent adverse event in the palbociclib-containing arm was grade 3 neutropenia (63.2% vs 2% in controls). Additionally, grade 2 and 3 fatigue, stomatitis, and diarrhea occurred in more patients on the palbociclib arm (28.3% vs 12.9%, respectively; 21.4% vs 1.2%, respectively; 37.5% vs 12.1%, respectively). The incidence of grade ≥ 4 adverse events was similar across study arms (12.3% vs 8.9% for palbociclib-containing arm vs control; P = .21). No treatment-related deaths were reported in either arm of the study.
At this time, overall survival remains immature. Median overall survival was not reached in the palbociclib arm vs 77 months in the control arm. The 5-year survival rates were 74.3% vs 69.8% in the palbociclib and control arms, respectively.
Additional Commentary
Virginia Kaklamani, MD
At a press conference where these late-breaking results were revealed, Virginia Kaklamani, MD, Co-Director of SABCS and leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center, said the median progression-free survival approaching 4 years “shows that patients can tolerate this treatment, and it continues to work for at least 4 years. The message from the control arm is that the progression-free survival of 29 months supports the common use of the addition of endocrine therapy in this patient population. Hopefully, we will be able to add palbociclib soon.”
Dr. Kaklamani continued: “This study is extremely important. We know that patients with HER2-positive disease live a long time. It’s a chronic disease that I describe as a marathon, not a sprint. Giving patients chemotherapy for a long time is detrimental to their quality of life. This regimen is more tolerable. We are trying to tackle two pathways at once with our treatments: the estrogen receptor pathway and the HER2 pathway. The good news is that these less toxic regimens help maintain quality of life for a long period of time,” she stated.
Sara A. Hurvitz, MD, FACP
EXPERT POINT OF VIEW
Formal discussant of the presentation on the AFT-38 PATINA trial, Sara A. Hurvitz, MD, FACP, of the University of Washington School of Medicine, Fred Hutchinson Cancer Center, Seattle, explained that data supporting the rationale for PATINA have been available for about 15 years. “The wide acceptance that HER2 is the driver of HER2-positive breast cancer may have limited the development of other therapies, with the exception of hormonal therapies for estrogen receptor–positive breast cancer. There is ample evidence of the crosstalk between the estrogen receptor and HER2. Inhibiting CDK4/6 plus anti-HER2 therapy is synergistic and has an anticancer effect,” she explained.
Dr. Hurvitz shared these comments on the PATINA results: “These data are impressive. The median progression-free survival of 29.1 months in the control arm is historic. Though it is important to note that since only patients with stable disease or a complete and partial response to induction chemotherapy were included, patients with primary resistance were eliminated. This may be the reason that progression-free survival was so high in both arms. The safety was reassuring, and we await patient-reported outcomes.”
“We will be moving away from a ‘one size fits all’ approach to HER2-positive breast cancer,” predicted Dr. Hurvitz. “This study provides definitive proof that there is benefit to targeting more than just the HER2 pathway in HER2-positive breast cancer. We need the right treatment for the right patient.”
DISCLOSURE: The AFT-38 PATINA trial was sponsored by Alliance Foundation Trials and conducted with support from Pfizer. Dr. Metzger reported no conflicts of interest. Dr. Kaklamani has served as a speaker for AstraZeneca, Daiichi Sankyo, Gilead Sciences, and Novartis; has served as a consultant to AstraZeneca, Celldex Therapeutics, Genentech, Lilly, Menarini, and Novartis; and has received research funding from Eisai. Dr. Hurvitz has received research funding from AstraZeneca, Bayer, Daiichi Sankyo, Genentech (Roche), G1 Therapeutics, Gilead Sciences, GSK, Immunomedics, Eli Lilly, Loxo Oncology, MacroGenics, Novartis, Pfizer, Sanofi, and Seagen; has received royalties from McGraw Hill, Sage Publications, Wiley, and Wolters Kluwer; has served on the data and safety monitoring board for Alliance Foundation Trials, Atossa Therapeutics, and the Quantum Leap Healthcare Collaborative; and has received honoraria from the Vaniam Group and OncLive. Her spouse owns stock in ROMTech.
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 + anti-HER2 therapy + endocrine therapy vs anti-HER2 therapy + endocrine therapy after induction treatment for hormone receptor-positive/HER2-positive metastatic breast cancer. 2024 San Antonio Breast Cancer Symposium. Abstract P2-03-20 (SESS-18111). Presented December 10, 2024.
