medwireNews: Women with hormone receptor (HR)-positive, HER2-positive locally advanced, metastatic, or recurrent breast cancer might benefit from a third- or later-line regimen of the CDK4/6 inhibitor abemaciclib in combination with trastuzumab and fulvestrant, findings from the phase 2 monarcHER trial suggests.
“This study provides clinical validation of the preclinical hypothesis suggesting that treatment with a CDK4 and CDK6 inhibitor might overcome acquired resistance to trastuzumab,” say Sara Tolaney, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-workers.
They report a significant progression-free survival (PFS) gain for the 79 patients who were randomly assigned to receive the triple regimen compared with the 79 patients who instead were given trastuzumab plus a physician’s choice of single-agent chemotherapy, such as vinorelbine or capecitabine, at 8.3 versus 5.7 months and a hazard ratio for progression or death of 0.67.
By contrast, the 79 patients who received abemaciclib plus trastuzumab had a statistically comparable PFS to that of the trastuzumab plus chemotherapy arm, at 5.7 months, the investigators report in The Lancet Oncology.
The triple regimen was also associated with a significant 3.2-fold higher likelihood of achieving a complete or partial response than trastuzumab plus chemotherapy (33 vs 14%) and a 2.7-fold greater likelihood of achieving a response or stable disease for at least 6 months (58 v 38%), whereas these significantly greater benefits did not occur with abemaciclib plus trastuzumab only.
Grade 3 and 4 treatment-related adverse events were more common with abemaciclib, trastuzumab, and fulvestrant than with trastuzumab plus chemotherapy, or abemaciclib plus trastuzumab, affecting 68%, 50%, and 48% of patients, respectively, with neutropenia the predominant side effect (27 vs 26 and 22%).
The researchers highlight patient-reported quality of life responses indicating that “significant and clinically meaningful” diarrhea was more common with the triple regimen than trastuzumab plus chemotherapy, alongside significant but not clinically meaningful nausea and vomiting, although these symptoms were all “typically transient.”
“The current study is noteworthy as it directly compared an endocrine-based regimen with standard-of-care chemotherapy in combination with trastuzumab, potentially offering a chemotherapy sparing treatment option,” the team concludes.
Nicolò Battisti and Alistair Ring, from The Royal Marsden NHS Foundation in Sutton, UK, remark in a linked comment that “it is not possible to evaluate the contribution of the CDK4 and CDK6 inhibitor” to the PFS benefit of the triple combination because the study lacked a fulvestrant plus trastuzumab arm.
They continue: “Given the tendency of HER2-positive breast cancer to involve the brain, an area of particular interest will be whether abemaciclib has an effect on [central nervous system] metastases.
“This study was not designed or powered to investigate this question, which is of interest in the context of other new targeted agents able to cross the blood–brain barrier in patients with HER2-positive breast cancer,” the commentators observe, noting “this question remains of great relevance to patients and their carers.”
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Lancet Oncol 2020; doi:10.1016/S1470-2045(20)30112-1
Lancet Oncol 2020; doi:10.1016/S1470-2045(20)30164-9