Palbociclib as adjunct maintenance therapy prolongs progression-free survival in some types of metastatic breast cancer

1. This randomized controlled trial found that, in patients with hormone-receptor-positive, HER2-positive metastatic breast cancer, the addition of palbociclib to standard therapy extended progression-free survival by more than one year.

2. Adverse events, most commonly neutropenia, were more frequent with palbociclib, though no deaths were determined to be related to the treatment. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Current first-line treatment for hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) breast cancer includes induction chemotherapy with trastuzumab and pertuzumab, followed by maintenance therapy with anti-HER2 and endocrine therapies. Some studies have implicated the cell cycle regulators cyclin D1 and cyclin-dependent kinases 4 and 6 (CDK4/6) in supporting tumor growth in HER2+ breast cancer. Thus, this randomized controlled trial aimed to study the efficacy and safety of palbociclib, a CDK4/6 inhibitor, as an additional first-line maintenance therapy for HR+/HER2+ metastatic breast cancer. All enrolled participants underwent induction therapy, then were randomly assigned to receive anti-HER2 and endocrine therapies with or without palbociclib. It was found that patients who received palbociclib survived approximately fifteen months longer than those who received only standard therapy. Nearly one-third of those receiving palbociclib had a confirmed response to therapy, compared to less than one-quarter receiving standard therapy. Adverse events were more frequent in those receiving palbociclib; moderately-severe adverse events were twice as frequent with palbociclib, mostly due to significantly higher rates of neutropenia and leukopenia leading to dose reduction in over half of palbociclib patients. Study strengths included adherence to current clinical guidelines for standard therapy and a relatively large sample size. Limitations included lack of racial diversity among participants and an open-label design. Overall, these results showed that palbociclib significantly prolonged progression-free survival in HR+/HER2+ metastatic breast cancer, although it was associated with more adverse events compared to standard therapy

Click to read the study in NEJM

Relevant Reading: Palbociclib and trastuzumab for HER2-positive metastatic breast cancer: final overall survival results of cohort A and B of SOLTI-1303-PATRICIA trial

In-Depth [randomized controlled trial]: This phase 3, open-label, randomized controlled trial studied adult patients with hormone-receptor positive, HER2-positive metastatic breast cancer to evaluate the efficacy of palbociclib as an additional maintenance therapy. Enrolled patients must have only undergone first-line treatment (4-8 cycles of trastuzumab, pertuzumab, and a taxane; or trastuzumab monotherapy with chemotherapy for 20% of participants) without evidence of disease progression. A total of 518 patients underwent stratified randomization based on prior therapy type and treatment response, and were assigned in a 1:1 ratio to receive either maintenance treatments (HER2 and endocrine therapies) with palbociclib or without palbociclib. Therapy was initiated no more than 12 weeks after the last induction treatment. The primary endpoint was progression-free survival, and secondary endpoints included confirmed objective response, overall survival, and safety. The median progression-free survival for the palbociclib group was 44.3 months (95% confidence interval [CI], 32.4 to 56.8 months) versus 29.1 months (95% CI, 23.3 to 38.6 months) in the standard therapy group. This corresponded to a hazard ratio for disease progression or death of 0.75 (95% CI, 0.59 to 0.96; unstratified p=0.02 and stratified p=0.03). Progression-free survival at 12, 24, and 48 months was 84.9%, 65.2%, and 46.5% in the palbociclib group and 73.2%, 55.3%, and 38.3% in the standard-therapy group. The percentage of participants experiencing a clinical benefit was 88.9% (95% CI, 84.4 to 92.4 percentage points) in the palbociclib group and 80.9% (95% CI, 75.6 to 85.6 percentage points). Adverse events occurred in all patients in the palbociclib group, and 94.4% of the standard-therapy group. Grade 3 and 4 adverse events occurred more than twice as frequently in the palbociclib group as compared to the control group, largely attributable to a greater incidence of neutropenia and leukopenia. Fatal events occurred at similar rates in both groups, and none were considered to be related to the trial regimen. Overall, it was shown that palbociclib was effective as maintenance therapy in conjunction with anti-HER2 and endocrine therapy for hormone-receptor-positive, HER2-positive metastatic breast cancer.

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