SAN ANTONIO – Pfizer's CDK4/6 inhibitor Ibrance (palbociclib) added to standard anti-HER2 and endocrine therapy may become a new standard of care for frontline maintenance treatment of hormone receptor (HR)-positive, HER2-positive metastatic breast cancer, based on Phase III data researchers shared last week.
The PATINA trial, data from which were presented on Thursday at the San Antonio Breast Cancer Symposium, compared the activity of Ibrance added to standard-of-care treatment, which could include Genentech's anti-HER2 therapy Herceptin (trastuzumab) with or without its other HER2-targeted drug Perjeta (pertuzumab) and endocrine therapy, compared to standard treatment alone. The Ibrance-containing regimen improved progression-free survival over standard treatment in patients who had metastatic breast cancer that was HER2 overexpressing and estrogen receptor (ER)- or progesterone receptor (PR)-positive, or was triple-positive.
Pfizer said in a statement that it plans to discuss the PATINA results with regulatory authorities. An approval in this setting would expand Ibrance's indication to both patients with HER2-positive and HER2-negative breast cancer in the first-line setting. Ibrance is currently approved in the US for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor in the frontline setting and in combination with fulvestrant in patients with disease progression following endocrine therapy.
The researchers began the trial based on preclinical research that suggested CDK4/6 inhibition could help prevent resistance to anti-HER2 therapies among HER2-positive breast cancer patients, Otto Metzger, an assistant professor at Harvard Medical School, said in presenting the PATINA results at the symposium.
"Resistance to therapy remains inevitable for the majority of patients with advanced disease," Metzger explained. "The cyclin D1-CDK4 axis is essential for initiation and maintenance of growth in HER2-positive cancers. This same axis drives resistance to the HER2 pathway blockade, so this combined CDK4/6 and HER2 inhibition has shown to be synergistic and have a profound anti-tumor activity in preclinical models."
The PATINA trial enrolled 518 patients who had completed initial induction chemotherapy and anti-HER2 therapy without evidence of disease progression. In the final progression-free survival analysis, presented on Thursday, patients in the Ibrance arm had a median progression-free survival of 44.3 months compared to 29.1 months in the control arm.
The addition of Ibrance to standard treatment also yielded a higher response rate, 29.2 percent versus 22.2 percent in the control arm.
Overall survival data were immature at the time of data cutoff. The five-year overall survival rate in the Ibrance arm was 74.3 percent compared to 69.8 percent in the control arm.
"Our results really reinforce the strong scientific rationale for overcoming resistance to anti-HER2 therapy and endocrine therapy with addition of palbociclib," Metzger said.
He added that the control arm in the study demonstrated higher-than-expected progression-free survival, but "in spite of that, we're seeing a 15.2 month improvement with the addition of palbociclib."
In PATINA, the toxicity in the Ibrance arm was manageable. "I would argue that palbociclib, when added to anti-HER2 and endocrine therapy may represent a new standard of care for patients diagnosed with HR-positive, HER2-positive breast cancer," Metzger continued.
Sara Hurvitz, senior VP and director of the Clinical Research Division at Fred Hutchinson Cancer Center, who was not involved with the PATINA study, said in a discussion of the results that how patients were selected for the trial likely contributed to the improved outcomes seen, even in the control arm. For example, by enrolling patients who had completed their initial induction chemo regimen, researchers may have selected for patients who didn't have de novo treatment resistance, she said.
"These patients weren't represented in PATINA and eliminating these patients with resistant disease is likely enriching the enrolled patients for the luminal subtype," she said, explaining that patients with this subtype of breast cancer often have a better prognosis. "It's a way to molecularly select your patients who would be appropriate for this particular treatment."
Hurvitz noted that the 44-month median progression-free survival in the Ibrance arm in the PATINA trial was "historic" and suggests that the frontline standard treatment for HR-positive, HER2-positive breast cancer may be changing.
"The frontline standard that is likely going to change very soon," she said, pointing to these results from PATINA and the forthcoming data from DESTINY-Breast09 that may establish AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) with Herceptin and Perjeta as a chemo-free first-line treatment option.
"It's time for us to move away from a one-size-fits-all approach to HER2-positive breast cancer," she said. "Today, we heard definitive proof that there are benefits to targeting more than just HER2 in HER2-positive breast cancer. CDK4/6 inhibitors, in my opinion, should be considered as part of the armamentarium for our patients, but nuanced patient selection is going to be needed."