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Everolimus–fulvestrant combination extends PFS in certain postmenopausal women with breast cancer
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SAN ANTONIO — The addition of everolimus to fulvestrant significantly extended PFS among postmenopausal women with hormone receptor–positive, HER-2–negative metastatic breast cancer resistant to aromatase inhibitor therapy, according to study results presented at San Antonio Breast Cancer Symposium.
However, women assigned the combination regimen experienced more grade 3 toxicities.
“While aromatase inhibitor therapy is a highly effective treatment in hormone receptor–positive metastatic disease, resistance to this therapy ultimately develops,” Noah S. Kornblum, MD, assistant professor of medicine at Albert Einstein College of Medicine and attending physician at Montefiore-Einstein Center for Cancer Care, said during a press conference. “One strategy for addressing aromatase inhibitor resistance is through targeting the P13K-AKT-mTOR pathway.”
In the randomized, double blind, phase 2 PrECOG 0102 trial, Kornblum and colleagues evaluated whether the effect of adding the mTOR inhibitor everolimus (Afinitor, Novartis) to fulvestrant.
The analysis included 130 postmenopausal women with hormone receptor–positive, HER-2–negative, inoperable, locally advanced or metastatic disease. All patients had ECOG performance status of 0 or 1, had normal organ function, were resistant to aromatase inhibitors and had undergone no more than one prior chemotherapy regimen for metastasis.
Treatment during the induction phase was administered in 28-day cycles. All patients received 500 mg fulvestrant on day 1 and day 15 of treatment cycle 1, and again on day 1 of cycles 2 through 12. Researchers randomly assigned patients to receive either 10 mg oral everolimus daily or placebo.
At week 48, patients who did not experience progression or unacceptable toxicity were allowed to proceed to the continuation phase of the study. Treatment assignment was unblended, and those patients continued to receive fulvestrant with or without everolimus.
Local treating physicians performed tumor measurements every 12 weeks.
PFS by investigator assessment served as the primary endpoint.
Results showed the addition of everolimus to fulvestrant significantly extended median PFS (10.4 months vs. 5.1 months; HR = 0.6; 95% CI, 0.40-0.92).
However, patients assigned the combination were more likely to experience grade 3 toxicities (48% vs. 14%). The most common grade 3 adverse events included stomatitis (9%), pneumonitis (6%), hyperglycemia (6%) and fatigue (5%).
Corticosteroid mouthwash prophylaxis — shown in prior studies to reduce risk for grade 1 to grade 2 stomatitis by more than half — was not used.
“We feel that our study provides additional evidence that adding everolimus to antiestrogen therapy in aromatase inhibitor–resistant disease improves clinical outcomes,” Kornblum said. “Our results are encouraging. I am always cautioning myself [about] irrational excitement when we see any new combination show benefit, but I think the excitement is real here.” – by Jennifer Southall
Reference:
Kornblum NS, et al. Abstract S1-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio, Texas.
Disclosure: Novartis funded this study. Kornblum reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Alberto J. Montero, MD, MBA
This study showed there was improvement with PFS with addition of everolimus. This finding was not surprising. We have other combinatorial approaches with antiestrogen treatment that have shown an improvement. It’s not practice changing for two reasons. First, it’s a randomized phase 2 trial. Second, everolimus has a significant toxicity to patients, much more than palbociclib (Ibrance, Pfizer) or the other CDK inhibitors, so I think that the landscape really is such that I think the CDK inhibitors are going to have more important place when combinatorial approaches – either with an aromatase inhibitor or fulvestrant – that would be the more logical pair than everolimus.
Perspective
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Stanley Lipkowitz, MD, PhD
To put this study in perspective, there is no OS benefit to adding this drug. There also is significant toxicity. Roughly 20% of patients who took everolimus stopped this drug due to toxicity vs. only about 8% of patients in the other arm.
There is a PFS benefit. This delays the addition of chemotherapy. That is not insignificant; it is an important outcome.
The question, then, is where does this fit in second-line treatment of metastatic breast cancer? It is very complicated.
The PALOMA-2 study is using fulvestrant but, instead of using everolimus, researchers used palbociclib (Ibrance, Pfizer), a CDK4/6 inhibitor. It improved PFS from roughly 4 months to 9 months. There were similar benefits to adding a CDK4/6 inhibitor, but there was a different spectrum of toxicity. The main toxicity in that setting was hematologic and white blood cell toxicity.
This does give us an additional choice for patients in the second line. Patients who progress on an aromatase inhibitor or perhaps an aromatase inhibitor plus a CDK4/6 inhibitor might benefit from fulvestrant plus everolimus, but that will have to be weighed with the toxicities of the particular therapies.
What’s sorely needed, then, is to be able to identify patients who might be more likely to benefit from palbociclib or one of the other CDK4/6 inhibitors vs. everolimus so we can select targeted therapies more specifically. As it stands, this is a choice, and it’s something that can improve PFS, which ultimately improves patients’ quality of life and delays the onset of chemotherapy.
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