NEW YORK – Results from the Phase II monarcHER study published last week in Lancet Oncology demonstrated that women with advanced HER2-positive breast cancer may benefit from a combination of three non-chemotherapy agents: the CDK4/CDK6 inhibitor abemaciclib (Lilly's Verzenio), the HER2-targeted therapy trastuzumab (Genentech's Herceptin), and the anti-estrogen therapy fulvestrant (AstraZeneca's Faslodex).
The study showed a significant improvement in progression-free survival among women treated with the three-drug combination compared with the combination of just abemaciclib and trastuzumab and the combination of trastuzumab and chemotherapy, respectively.
"The 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," wrote the study authors, led by Sara Tolaney of the Dana Farber Cancer Institute, in their published paper.
Patients enrolled in the trial, all of whom had advanced hormone receptor-positive, HER2-positive breast cancer, had already received at least two HER2-targeted therapies, either in combination with chemotherapy or endocrine therapy or as a single agent. The study authors noted that the disease progression these women had experienced after prior treatment with HER2-targeted agents was likely due to acquired resistance mediated by effectors downstream of the HER2 receptor, and that, after acquired resistance to multiple anti-HER2 agents, many women with advanced HER2-positive breast cancer lack satisfactory treatment options.
This added further significance to the study, positioning the three-drug combination as a potential option for a patient population with a particular need. "The patients participating in monarcHER represent a heavily pretreated population," wrote the study authors, noting that "a chemotherapy-free treatment option in an advanced and heavily pretreated patient population would probably be of interest to both patients and their physicians."
The monarcHER study randomly assigned a total of 237 patients into three groups. Patients in the first group, group A, were treated with the three-drug abemaciclib, trastuzumab, and fulvestrant combination; patients in group B were treated with the two-drug abemaciclib and trastuzumab combination; and patients in group C were treated with trastuzumab combined with the treating physician's choice of standard-of-care chemotherapy, for which the most common agents used were vinorelbine, capecitabine, eribulin, and gemcitabine. Researchers then compared group A to group C, and then, contingent on whether group A saw a significant benefit over group C, went on to compare group B to group C.
According to the published results, group A experienced significantly longer progression-free survival compared to group C. Among patients treated with the three-drug combination, the median progression-free survival was 8.3 months, compared with 5.7 months for patients treated with trastuzumab and chemotherapy.
There was no significant difference in progression-free survival between group B, including patients treated with abemaciclib and trastuzumab without fulvestrant, and group C, the patients treated with trastuzumab and chemotherapy.
Overall response was measured as a secondary endpoint, derived from both responses while on the treatment and in the short-term follow-up period prior to the induction of any post-study treatment. For this measure, the study authors noted that group A experienced an overall response rate that was more than double that of group C.
In terms of toxicities and adverse events, the study authors noted that abemaciclib was generally well-tolerated, despite the fact that, numerically, more adverse events of grade 3 and above were noted in the three-drug combination group. The authors suggested that this could be due to the fact that group A had a longer duration of treatment than group C, allowing more time for events to emerge. Authors pointed out as well that deaths on treatment and dose discontinuations from adverse events were balanced between groups A and C.
"On review of all available data … it is reasonable to suppose the superiority of group A compared with group C is owing to the synergism rather than the addition of fulvestrant alone," wrote the study authors, pointing to the fact that activity was also seen with the abemaciclib and trastuzumab combination in group B.
The results lent validity to the preclinical hypothesis that treatment with a CDK4/CDK6 inhibitor might overcome acquired resistance to trastuzumab. The biological rationale for this, as hypothesized through preclinical research in genetically engineered mouse models, cell lines, and patient-derived xenografts of HER2-therapy resistant breast cancer, was that the CDK4/CDK6 pathway can mediate resistance to HER2-targeted therapies, and that this resistance, in turn, can be overcome by inhibiting CDK4 and CDK6 with abemaciclib.
Though the study's primary endpoint was progression-free survival, final data relating to the key secondary endpoint of overall survival will be analyzed after approximately 158 deaths have occurred in the intent-to-treat population.
The study authors noted that larger studies are warranted. They pointed out as well that the monarcHER study was limited in the sense that its design did not allow for the isolation of the contributing treatment effect of fulvestrant, and to do so would require a fourth treatment group examining the combination of fulvestrant and trastuzumab.
An additional limitation of the monarcHER study was that it did not specifically examine the effects of the treatment groups on brain metastases. Since recurrence in the brain is of particular concern for patients with HER2-positive breast cancer, Tolaney said that "there is interest in further studies of abemaciclib and anti-HER2 therapy for patients with HER2-positive brain metastases." She noted that, in terms of plans for future research into CNS activity, "discussions are ongoing."
Finally, although there was no mention of financial toxicity in the monarcHER study, the question remains as to the cost burden that may arise with a three-drug combination consisting of targeted agents. "No financial analyses were conducted to compare cost of chemotherapy and anti-HER2 therapy with abemaciclib plus fulvestrant plus trastuzumab," said Tolaney. But when it comes multi-drug combinations in precision oncology, financial toxicity has increasingly been cited as an issue that warrants careful consideration. According to Lilly, the list price for abemaciclib alone is $12,377.12 per month.