Late-breaking data from 2 clinical trials presented at ESMO 2019 will likely change the treatment paradigm for pre- or postmenopausal women with hormone receptor (HR)-positive, HER2-negative breast cancer, regardless of menopausal status. The MONALEESA-3 study and the MONARCH-2 study showed an improved overall survival (OS) with the addition of the CDK4/6 inhibitor ribociclib (Kisqali) or abemaciclib (Verzenio) to endocrine therapy as first- or second-line therapy. The results were presented at the Presidential Session of the meeting.
“I had the good fortune to work with many of you in testing targeted therapy with Herceptin, and I think the results we are seeing are as exciting as we saw back in those days,” said Dennis J. Slamon, MD, PhD, lead investigator of the MONALEESA-3 clinical trial and Director, Clinical/Translational Research, and Revlon/UCLA Women’s Cancer Research Program, Jonsson Comprehensive Cancer Center, CA. Dr Slamon pioneered the development of trastuzumab (Herceptin) and is the recipient of the 2014 Giants of Cancer Care in Breast Cancer recognition.
The results of MONALEESA-3 and MONARCH-2 join the ALOMA-3 clinical trial of palbociclib (Ibrance)—now 3 different CDK4/6 inhibitors have demonstrated a survival benefit in HR-positive, HER2-negative breast cancer. Although this news is a game-changer, questions remain, such as is any 1 of the 3 CDK4/6 agents preferred, and if so, in the first- or second-line setting? What is the best endocrine therapy for a CDK4/6 inhibitor in the first-line setting—an aromatase inhibitor or fulvestrant (Faslodex)? And what is the best sequence after CDK4/6 inhibitor plus endocrine therapy?
Ribociclib: MONALEESA-3
Adding ribociclib to fulvestrant reduced mortality risk by approximately 28% versus placebo plus fulvestrant in postmenopausal patients with advanced breast cancer, according to a survival analysis of the phase 3 MONALEESA-3 study.
At a median follow-up of 39.4 months, the median OS was not reached in the ribociclib arm versus 40 months with placebo (P = .0045), a significant difference based on the prespecified significance of .01129, Dr Slamon said.
“These data show that there is a significant but also clinically meaningful benefit in terms of prolongation of progression-free survival [PFS] and now OS, regardless of whether the patient is premenopausal or postmenopausal, and regardless of whether they received their treatment in the frontline setting or subsequently,” Dr Slamon noted.
The study included 726 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who were randomized in a 2:1 ratio to ribociclib 600 mg daily in a 3-weeks-on, 1-week-off schedule plus fulvestrant 500 mg daily or placebo. Patients were stratified by liver or lung metastases status and previous endocrine therapy use.
“Essentially half of patients were getting their therapy in the first-line setting,” said Dr Slamon. “In other words, they had not received any therapy for metastatic breast cancer, and they were being compared with those who were getting fulvestrant in the same setting.” The second half of the patients received the study treatment in the second-line setting.
The baseline patient characteristics were generally balanced between arms. Approximately 61% of patients (median age, 63 years) had visceral disease and 21% had bone-only metastasis. Approximately 60% of patients had previously received endocrine therapy in the neoadjuvant setting, and 16.5% in the placebo arm and 22.7% in the ribociclib arm received it in the adjuvant setting. At the data cutoff on June 3, 2019, 25% of patients receiving ribociclib continued to use that treatment compared with only 13% of patients in the placebo arm.
The OS was superior with ribociclib plus fulvestrant in the first-line setting and in the early-relapse or second-line settings. In the first-line setting, the median OS with ribociclib plus fulvestrant was not reached versus 45.1 months with placebo plus fulvestrant. In the early-relapse or second-line setting, the median OS with ribociclib plus fulvestrant was 40.2 months versus 32.5 months in the placebo arm.
The CDK4/6 inhibitor also improved OS across several patient subgroups, including those with bone lesions, no lung or liver metastases, and those with metastatic disease.
No new safety signs were observed. The major grade 3 or 4 adverse events with ribociclib versus placebo included neutropenia (57.1% vs 0.8%, respectively), hepatobiliary toxicity (13.7% vs 5.8%), pulmonary disorders (0.2% vs 0%), and QTc prolongation (3.1% vs 1.2%).
ESMO Expert Comment
Nadia Harbeck, MD, PhD, Head of Breast Center, University of Munich, Germany, commented on the clinical implications at a press conference.
“MONALEESA-3, for the first time, gives us data in the first- and second-line setting. For patients who have not been receiving any endocrine therapy before that, that makes it highly clinically meaningful, because we were always struggling with whether to give these drugs in the first- or second-line setting. Now, we see there is a first-line survival benefit; that should be the new standard of care—a CDK4/6 inhibitor in the first-line setting. The data are highly clinically meaningful, and I think they’re going to make a huge impact in how we treat metastatic breast cancer.”
Abemaciclib: MONARCH-2 Second-Line Setting
In the phase 3 MONARCH-2 clinical trial, the addition of the CDK4/6 inhibitor abemaciclib to endocrine therapy (with fulvestrant) led to a median 9.4-month OS benefit versus placebo plus fulvestrant in women with HR-positive, HER2-negative advanced breast cancer that progressed with endocrine therapy. At a median follow-up of 47.7 months, the median OS was 46.7 months in the abemaciclib arm versus 37.3 months in the placebo arm (P = .0137).
“The addition of abemaciclib to fulvestrant provided a statistically significant OS improvement in patients with HR-positive, HER2-negative breast cancer who had progressed on prior endocrine therapy,” said lead author George W. Sledge Jr, MD, Chief, Division of Oncology, Stanford University Medical Center, CA. “This OS benefit is consistent across subgroups, including patients with poor prognostic factors, such as visceral metastasis and primary endocrine therapy resistance. Abemaciclib significantly delayed the receipt of subsequent chemotherapy in a subsequent analysis.”
The MONARCH-2 study included 669 pre-, peri-, or postmenopausal women with HR-positive, HER2-negative advanced breast cancer resistant to endocrine therapy who were randomized in a 2:1 ratio to abemaciclib plus fulvestrant or to placebo plus fulvestrant. Abemaciclib 150 mg was administered twice daily on a continuous schedule and fulvestrant 500 mg was given twice daily continuously.
Study eligibility criteria included disease relapse during neoadjuvant endocrine therapy, within 1 year of adjuvant endocrine therapy, or disease progression during first-line endocrine therapy for advanced breast cancer. Those who received previous chemotherapy for advanced disease or ≥1 lines of endocrine therapy were excluded.
The updated median PFS with abemaciclib plus fulvestrant and with placebo plus fulvestrant was 16.9 months and 9.3 months, respectively (P <.0001). The 3-year PFS rates were 29.9% and 10.1%, respectively. The addition of abemaciclib also improved the time to second disease progression, for a median of 23.1 months versus 20.6 months in the placebo arm.
The median chemotherapy-free survival was 25.5 months with abemaciclib and 18.2 months with placebo. The abemaciclib-fulvestrant combination also led to a 60% delay in time to chemotherapy: the median time to chemotherapy was 50.2 months with abemaciclib versus 22.1 months with placebo (P <.0001).
The side-effect profile of abemaciclib was consistent with previously reported events. Common hematologic grade ≥3 side effects included neutropenia (29.9%), anemia (9.1%), and leukopenia (11.1%). No new cases of febrile neutropenia were reported, and 1.4% of patients discontinued treatment because of diarrhea.
ESMO Expert Comment
At the press conference, Dr Harbeck also commented on these practice-changing results. “Fifty months to chemotherapy, this is a game changer in metastatic breast cancer. The MONARCH-2 trial shows, for the first time, a significant OS advantage in a purely second-line cohort of pre- and postmenopausal patients,” she said.
“It’s the first time we see OS data for abemaciclib, which is 1 of the 3 CDK4/6 inhibitors, and the delta of 10 months is clinically meaningful. Also, the fact that patients live for 46 months with their metastatic disease in the second-line setting with abemaciclib is meaningful,” Dr Harbeck added.