Researchers are exploring the safety and efficacy of the novel CDK 4/6 inhibitor ribociclib (LEE011) in the phase III MONALEESA- 7 trial.
Debu Tripathy, MD
Although targeting cyclin-dependent kinase (CDK) 4/6 has proved to be a successful strategy in the management of postmenopausal women with hormone receptor (HR)— positive, HER2-negative advanced breast cancer, there is an unmet need for premenopausal patients in similar treatment settings.
As a result, researchers are exploring the safety and efficacy of the novel CDK 4/6 inhibitor ribociclib (LEE011) in the phase III MONALEESA- 7 trial (NCT02278120). Patients with HR-positive, HER2-negative breast cancer are randomized to receive ribociclib orally at 600 mg daily in combination with an aromatase inhibitor or tamoxifen plus goserelin or the same antihormonal regimen plus placebo.
“The MONALEESA-7 study is the first trial that is specifically designed for premenopausal patients— an area that we don’t know much about,” said Debu Tripathy, MD, who is the study’s principal investigator.
“Here, the treatment is either tamoxifen or an aromatase inhibitor, but patients are also receiving goserelin to medically suppress the ovaries. “If patients have not previously had hormonal therapy in the adjuvant setting, they can choose tamoxifen or an aromatase inhibitor, or if they have recently been on tamoxifen or an aromatase inhibitor, they would receive the alternate drug,” Tripathy said.
Ribociclib already has scored a clinical trial success in breast cancer, according to Novartis, which is developing the drug.
The MONALEESA-2 trial (NCT01958021), which was testing the drug in combination with letrozole, met its primary endpoint of significantly extending progression-free survival (PFS) compared with letrozole alone, promopting an independent data monitoring committee to recommend that the study be stopped early, the company said. That trial recruited 668 postmenopausal HR-positive, HER2-negative patients who have had no prior therapy for advanced disease.
The MONALEESA-3 study (NCT02422615) is examining second-line therapy with fulvestrant with or without ribociclib, in an effort to better understand what impact the drug would have with fulvestrant in postmenopausal patients with advanced HR-positive, HER2-negative disease.
ER indicates estrogen receptor; NSAI, nonsteroidal aromatase inhibitor; PR, progesterone receptor.
Tripathy, chair of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, put the MONALEESA-2 trial in the context of the need for new therapies for the premenopausal patient population. CDK 4/6 activity helps regulate the cell cycle, and dysregulation of the pathway results in increased proliferation.
“There has been a lot of interest in new directions for HR-positive breast cancer,” he said. “Clearly, hormonal therapy is effective. Yet, in the advanced setting, most patients do unfortunately develop resistance to hormonal therapy.
As we understand the mechanisms of hormonal resistance, new therapies have been developed that are targeting biological pathways, in addition to hormonal therapy, that are showing improvements in disease-free survival.”
Palbociclib (Ibrance) became the first CDK 4/6 inhibitor to gain FDA approval in February 2015 in combination with letrozole as initial endocrine- based therapy for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.
A year later, the FDA approved the drug in combination with fulvestrant for women with disease progression following endocrine therapy based on clinical trial data involving pre- and postmenopausal women. Among 521 participants, 80% were postmenopausal, according to the FDA.
In the MONALEESA-7 study, researchers hope to expand knowledge about premenopausal patients in several ways. Biomarker analyses with tissue and serial blood specimens will be conducted to determine mechanisms of response and identify patients who are most likely to respond to ribociclib. Additionally, Tripathy said, researchers will capture quality-of-life data, as patients will experience immune suppression.
“This is very important, because a good portion of our patients are premenopausal at the time that they progress,” Tripathy said of the study’s significance. “We will be able to explore this uniquely in that group of patients. We also need to learn more about the biology of the disease and the biology of resistance. We think that this information is going to be very important.
"In other parts of the world, patients are diagnosed at younger ages,” Tripathy added. “In the United States, there are populations of patients at younger ages—African American women and women who have genetic susceptibility. There are special populations for which we really need to answer these questions.”
The trial is accruing “very well,” according to Tripathy, and is open worldwide. Readout from the study is expected in late 2017Exclusion criteria include inflammatory breast cancer, CNS metastases, or prior hormonal therapy.
The study’s primary endpoint is PFS, with secondary endpoints being overall survival, clinical benefit rate, safety, time to response, duration of response, and overall response rate.
“It is important to remember that premenopausal patients are heavily represented in patients who recur, and we don’t have proven treatments for them yet,” Tripathy said. “While it may make sense that ovarian blockade and treatment is going to be helpful, we don’t know that that’s the case.
“Tumors may be different when they arise in the premenopausal setting,” hes aid. “The effect of estrogen and ovarian suppression may be a prolonged effect; it may not reverse right away. Therefore, it is very important for us to understand both the activity and the side effects.”