Alessandro Riva, MD
The combination of the CDK4/6 inhibitor ribociclib (LEE011) and letrozole significantly improved progression-free survival (PFS) compared with letrozole alone for patients with HR-positive, HER2-negative advanced breast cancer, according to findings from the phase III MONALEESA-2 study.
The improvement in PFS was identified at an interim analysis by an independent data monitoring committee, which recommended the study should be stopped, according to the developer of ribociclib, Novartis. Data from the study have not yet been released and are being prepared for presentation at an upcoming medical meeting.
"We are excited that these results validate our belief that LEE011 in combination with letrozole can be a beneficial treatment option for women diagnosed with HR+/HER2- advanced breast cancer," Alessandro Riva, MD, Global Head, Oncology Development and Medical Affairs, Novartis Oncology, said in a statement. "Novartis is dedicated to continuing to discover and develop innovative targeted therapies that help improve and extend the lives of women living with this disease."
The phase III trial enrolled 668 postmenopausal women with advanced breast cancer who had not yet received prior therapy for advanced disease. Letrozole was administered at 2.5 mg per day along with placebo or ribociclib at 600 mg per day for 3 weeks followed by 1 week off. The primary endpoint of the study was PFS. Secondary outcome measures focused on overall survival (OS), overall response rates, and safety.
Adverse events (AEs) observed in the study were consistent with previous reports for ribociclib. Although the trial is being stopped, data will continue to be assessed for OS. Following the positive analysis, Novartis will now begin approval discussions with the FDA and other global regulatory agencies.
Prior to the phase III study, a phase Ib study looked at the combination of letrozole with ribociclib (n = 13) or the PI3K alpha inhibitor alpelisib. The median age of patients enrolled in the letrozole/ribociclib arm was 58 years, and 31% had received >5 prior regimens, which included prior endocrine therapy (85%). The median number of prior therapies was 3.
One patient experienced a partial response (7.7%) and 3 had stable disease, for a disease control rate of 31%. An additional 5 patients were without measurable disease or progression and 3 had progressed.
The most common all grade AEs were neutropenia (85%), nausea (39%), leukopenia (39%), fatigue (23%), anemia (23%), lymphopenia (23%), and increased creatinine (15%). The most common grade 3/4 AEs were neutropenia (46%), lymphopenia (23%), and leukopenia (15%), which were all suspected to be study treatment-related.
A number of clinical trials continue to assess ribociclib as a treatment for patients with breast cancer. The phase III MONALEESA-3 trial is exploring ribociclib with fulvestrant for patients with advanced breast cancer following one prior line of endocrine therapy. The primary endpoint of the study is PFS. The trial plans to enroll 660 participants (NCT02422615).
The ongoing phase III MONALEESA-7 trial is currently exploring ribociclib with tamoxifen and goserelin or a non-steroidal aromatase inhibitor and goserelin for patients with HR+/HER2- advanced breast cancer. The primary endpoint of the study, which plans to enroll 660 patients, is also PFS (NCT02278120).
“The MONALEESA-7 study is the first trial that is specifically designed for premenopausal patients—an area that we don’t know much about,” lead investigator Debu Tripathy, MD, from the MD Anderson Cancer Center, told OncLive
. “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.”
In earlier settings, a phase II study is looking at neoadjuvant treatment with letrozole and ribociclib for patients with ER+/HER2- early breast cancer. This study is exploring the rate of preoperative endocrine prognostic index score 0 as the primary endpoint. Secondary endpoints will also assess pathologic complete response (NCT02712723).
Munster PN, Hamilton EP, Estevez LG, et al. Ph IB study of LEE011 and BYL719 in combination with letrozole in ER+, HER2- breast cancer. J Clin Oncol. 2014;32 (suppl 26; abstr 143).