In the phase 3 MONALEESA-7 trial, patients with hormone receptor–positive, HER2-negative breast cancer had a significant improvement in overall survival and chemotherapy delay when treated with ribociclib plus endocrine therapy compared with placebo.
In the phase 3 MONALEESA-7 trial (NCT02278120), patients with hormone receptor (HR)–positive, HER2-negative breast cancer had a significant improvement in overall survival (OS) and chemotherapy delay when treated with ribociclib (Kisqali) plus endocrine therapy compared with placebo, according to results presented during the 2020 San Antonio Breast Cancer Symposium.1
At a median follow-up of 53.5 months (range, 46.9-66.4), the median OS with ribociclib plus endocrine treatment was 58.7 months vs 48.0 months with placebo/endocrine therapy (HR, 0.763; 95% CI, 0.608-0.956), translating to a 24% relative reduction in the risk of death with the CDK4/6 inhibitor.
Moreover, data from a subgroup analysis examining survival in relation to endocrine partner, results showed that patients who received a nonsteroidal aromatase inhibitor (NSAI) experienced a median OS of 58.7 months with ribociclib/endocrine therapy vs 47.7 months with placebo/endocrine therapy (HR, 0.798; 95% CI, 0.615-1.04). In those who received tamoxifen, the median OS had not yet been reached with ribociclib vs 49.3 months with placebo (HR, 0.705; 95% CI, 0.453-1.097).
“A consistent significant OS benefit with ribociclib plus endocrine therapy was demonstrated after a longer median follow-up of 53.5 months. With a median OS of 58.7 months in the ribociclib arm, this is the longest median OS [that we have seen] among the phase 3 trials for HR-positive, HER2-negative advanced breast cancer,” Debu Tripathy, MD, professor and chairman of the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in a poster presentation during the meeting. “Therefore, this exploratory analysis confirms the benefit and continued use of ribociclib in the first-line setting for pre- or perimenopausal patients with HR-positive, HER2-negative advanced disease.”
In the multicenter, double-blinded, placebo-controlled phase 3 MONALEESA-7 trial, investigators set out to evaluate the efficacy of ribociclib in pre- and perimenopausal patients with HR-positive, HER2-negative advanced breast cancer. To be eligible to participate, patients needed to have received at least 1 previous line of chemotherapy for advanced disease and they could not have been administered prior endocrine treatment.
A total of 672 patients were randomized 1:1 to receive either ribociclib at a daily dose of 600 mg 3-weeks-on/1-week-off (n = 335) or placebo (n = 337) in combination with goserelin plus either a NSAI or tamoxifen. The primary end point of the trial was progression-free survival (PFS), and key secondary end points comprised OS, health-related quality of life, overall response rate (ORR), time to definitive deterioration of the ECOG performance status, PFS2, and safety, among others.
Patient characteristics were found to be well balanced between the 2 treatment arms. The median age of participants in the investigational arm was 43 years.2 Moreover, 55.8% were white, 29.6% were Asian, and 8.7% were black, Native American, or other. The race of 6.0% of patients was unknown. The ECOG performance status of 73.1% of patients was 0; it was 1 in 26.0%, and unknown for the remaining 0.9%. More than half, or 57.6%, of patients had visceral metastases, with 24.2% of them having bone-only metastases.
Earlier data showed that ribociclib plus endocrine therapy was found to significantly improve PFS and OS compared with placebo/endocrine therapy in this patient population. Specifically, the median PFS was 23.8 months in the investigational arm vs 13.0 months in the control arm (HR, 0.55; 95% CI, 0.44-0.69; P < .0001).3,4 At a median follow-up of 34.6 months, the median OS reported in the final protocol-specified OS analysis had not yet been reached in the ribociclib arm vs 40.9 months in the placebo arm (HR, 0.71; 95% CI, 0.54-0.95; P = .00973).
“After the prior analysis, patients were unblinded and 15 patients in the placebo arm crossed over to receive ribociclib,” Amy S. Clark, MD, MSCE, assistant professor of medicine at the Hospital of the University of Pennsylvania, commented in a poster spotlight session during the meeting. “The median OS had not been reached in the ribociclib group in that initial OS analysis, so I do think it was important to continue to follow these results.”
Results from an exploratory subgroup analysis presented at the meeting proved to be consistent with the OS data reported for the overall patient population. However, investigators noted that this should be interpreted with caution because of the small numbers of patients, relatively wide confidence intervals, and a lack of statistical power, said Tripathy.
As of the June 29, 2020 data cutoff, 21.2% of patients on the ribociclib/endocrine therapy arm and 9.2% of those on the placebo arm were still receiving treatment. Almost 80% (78.8%) of patients on the investigative arm had ended treatment vs 90.8% of those on the control arm.
On the ribociclib arm, the majority of patients, or 62.7%, discontinued due to disease progression,” noted Tripathy. Additionally, 6.3% of these patients discontinued due patient/guardian decision, 3.6% due to physician decision, 4.8% due to an adverse effect (AE), 0.9% due to death, and 0.6% were lost to follow-up.
Moreover, 77.3% of those on the ribociclib/endocrine therapy arm vs 78.1% of those on the placebo/endocrine therapy arm went on to receive subsequent therapy. The most common first subsequent therapies were chemotherapy alone and hormone therapy alone.
Subsequent treatments received in the investigative and control arms included chemotherapy (22.3% vs 28.4%, respectively), chemotherapy plus hormone therapy or other therapy (10.2% vs 10.1%), hormone therapy alone (27.7% vs 18.3%), hormone therapy plus other therapy (15.2% vs 18.0%), or other treatment (1.9% vs 3.3%).
Moreover, more patients on the placebo arm went on to receive a CDK4/6 inhibitor following treatment discontinuation. Almost 13% of patients on the investigative arm went on to receive another CDK4/6 inhibitor vs 26.1% of those on the control arm. Among the patients on the investigative arm, 9.5% received palbociclib (Ibrance), 2.3% received ribociclib, and 1.5% received abemaciclib (Verzenio). In the control arm, 21.9%, 3.9%, and 0.7% of patients received palbociclib, ribociclib, or abemaciclib, respectively.
The median time to chemotherapy was 50.9 months with ribociclib plus endocrine therapy vs 36.8 months with placebo plus endocrine therapy (HR, 0.694; 95% CI, 0.556-0.867). Moreover, the median chemotherapy-free survival in the investigative and control arms was 42.4 months vs 26.4 months, respectively (HR, 0.666; 95% CI, 0.550-0.808). Lastly, the median PFS2 with ribociclib was 44.2 months vs 31.0 months with placebo (HR, 0.683; 95% CI, 0.560-0.834).
The toxicities in the safety population proved to be consistent with those observed in the primary and final OS analyses, according to Tripathy. AEs of special interest in the ribociclib and placebo arms included all-grade neutropenia (77.9% vs 10.7%, respectively), leukopenia (35.5% vs 5.9%), anemia (22.7% vs 11.6%), hepatobiliary toxicity (29.3% vs 23.7%), QTc prolongation (12.8% vs 6.5%), and interstitial lung disease/pneumonitis (0.6% vs 0%, respectively).
The most commonly reported grade 3 or higher AE in the ribociclib arm was neutropenia (53.1%, grade 3; 11.6%, grade 4). In the control arm, hepatobiliary toxicity was the most frequently experienced grade 3 effect (6.8%), while neutropenia (0.9%) was the most common grade 4 toxicity.
“The OS benefit of those receiving ribociclib and endocrine therapy, regardless of the endocrine therapy partner, was sustained in this longer-term follow-up,” concluded Clark. “The addition of ribociclib also lengthens time to chemotherapy and chemotherapy-free survival, which I think is an incredibly important outcome for these patients who live for many years and who would like to delay the time to chemotherapy for as long as possible. I believe that these data are continued evidence that ribociclib should be considered for use in pre- and perimenopausal women with newly diagnosed [estrogen receptor]–positive metastatic breast cancer.”
1. Tripathy D, Im S-A, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with endocrine therapy (ET) +/- ribociclib. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PD2-04. https://bit.ly/33WH2ly.
2. Tripathy D, Im S-A, Colleoni M, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a nonsteroidal aromatase inhibitor in premenopausal women with hormone receptor—positive, HER2-negative advanced breast cancer: results from the randomized phase 3 MONALEESA-7 trial. Presented at: 35th Annual Miami Breast Cancer Conference; March 8-11, 2018; Miami, FL. Abstract 626.
3. Tripathy D, Im S-A, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. doi:10.1016/S1470-2045(18)30292-4
4. Im S-A, Lu Y-S, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi:10.1056/NEJMoa1903765