MONALEESA-2 Subgroup Analysis Highlights Survival Benefit With Ribociclib/Letrozole in HR+ Breast Cancer

Joyce O’Shaughnessy, MD

The frontline combination of ribociclib (Kisqali) and letrozole significantly prolonged overall survival (OS) over letrozole alone in a subset of patients with hormone receptor–positive, HER2-negative advanced breast cancer who had de novo metastatic disease or late recurrence from neoadjuvant therapy, according to data from an exploratory analysis of the phase 3 MONALEESA-2 trial (NCT01958021).¹

Findings presented at the 2023 ESMO Breast Cancer Annual Congress showed that at a median follow-up of 79.8 months, the doublet (n = 275) resulted in a median OS of 69.2 months vs 54.3 months with letrozole alone (n = 270) in this subgroup, translating to a 25% relative reduction in the risk of death (HR, 0.75; 95% CI, 0.60-0.93; P = .005). This hazard ratio proved to be consistent with what had been observed in the overall trial population.

“The median OS for patients with de novo metastatic disease or late recurrence surpassed that of the overall population for both arms, reaching almost 6 years in the ribociclib arm,” lead study author Joyce O’Shaughnessy, MD, of the Baylor University Medical Center and US Oncology Research Network in Dallas, Texas, and colleagues, wrote in a poster on the data. “An [approximate] 15-month improvement with first-line ribociclib over placebo was demonstrated.”

In this subgroup, the combination of ribociclib and letrozole also improved progression-free survival (PFS) over letrozole alone, with a median PFS of 30.3 months vs 16.7, respectively, translating to a 43% reduction in the risk of disease progression or death in this population (HR, 0.57; 95% CI, 0.46-0.70; P < .001).

The phase 3 MONALEESA-2 trial enrolled postmenopausal women with locally confirmed hormone receptor–positive/HER2-negative, recurrent or metastatic breast cancer who did not receive prior systemic treatment in the advanced setting.2 To be eligible for enrollment, patients were required to have an ECOG performance status of 0 or 1, measurable disease by RECIST v1.1 criteria, as well as acceptable bone marrow and organ function.

Patients were allowed to have previously received neoadjuvant endocrine therapy, provided that they had a treatment-free interval (TFI) of greater than 12 months. TFI was defined as the time from the end of neoadjuvant endocrine therapy until disease recurrence. ^1,2

Study participants were randomly assigned to receive oral ribociclib at a daily dose of 600 mg as part of a 3-weeks-on/1-week-off schedule plus continuous letrozole given at a daily dose of 2.5 mg, or placebo plus letrozole at the same dose and schedule.¹

The primary end point of the trial was PFS per investigator assessment, and OS served as a key secondary end point.

Final OS data from the MONALEESA-2 trial were previously published in the New England Journal of Medicine, and showed that the median OS in the overall patient population was 63.9 months (95% CI, 52.4-71.0) with ribociclib plus letrozole (n = 334) vs 51.4 months (95% CI, 47.2-59.7) with letrozole alone (n = 334; HR, 0.76; 95% CI, 0.63-0.93; 2-sided P = .008).²

Patients with early recurrence, or a TFI greater than 12 months, are known to have poorer responses to first-line treatment, with similar outcomes to pretreated patients with advanced breast cancer.¹ At the 2023 ESMO Breast Cancer Annual Congress, investigators reported survival and safety data from the subgroup analysis of MONALEESA-2 patients with de novo metastatic disease or late recurrence. ¹

Patients with de novo metastatic disease had not received any prior therapy for their disease. This group included those who did not experience first recurrence/progression or first recurrence within 90 days of diagnosis and did not have previous antineoplastic medication being administered. Those with late recurrence had a TFI of greater than 12 months from neoadjuvant therapy completion; they could not have received treatment for advanced or metastatic disease.

In the subgroup analysis, investigators assessed OS, PFS, time to chemotherapy or death (TTC), chemotherapy-free survival (CFS), and safety. All end points were assessed using the Kaplan-Meier method, and a stratified Cox proportional hazards mode was used to estimate hazard ratios.

Of the 688 patients enrolled in MONALEESA-2, 18.4% displayed early disease recurrence and were not enrolled in the subgroup analysis. Of the remaining 545 patients, 275 were in the ribociclib arm and 270 were in the placebo arm. In the investigative arm, 41.5% of patients had de novo metastatic disease, and 58.5% had late recurrence; in the placebo arm, these percentages were 41.9% and 58.1%, respectively.

Baseline characteristics in those with de novo metastatic disease or late recurrence were noted to be overall well balanced between the arms. The median age of patients in both arms was 64 years. The percentage of patients who were older than 65 years was 50.9% in the ribociclib arm vs 51.5% in the placebo arm; the percentages of patients aged 65 years or younger were 49.1% and 48.5%, respectively. Spanning the arms, most patients were Caucasian (79.3% vs 84.1%) and had an ECOG performance status of 0 (61.5% vs 58.9%).

No patients in the ribociclib arm received prior neoadjuvant endocrine therapy vs 0.7% of those in the placebo arm. Prior adjuvant endocrine therapy had been received by 43.6% of those in the ribociclib arm and 40% of those in the placebo arm.

In those with late recurrence (n = 318), the median TFI was 52.8 months. The combined disease-free interval (DFI), which was defined as time from initial diagnosis to disease recurrence, was greater than 5 years in 85.2% of patients and greater than 10 years in 46.5%.

In those with de novo metastatic disease or late recurrence, the median TFI with ribociclib plus letrozole was 52.6 months, and 56.5% of patients had a TFI of at least 36 months. The median TFI with letrozole alone in this population was 54.4 months, with 51% of patients having a TFI of at least 36 months. The percentage of patients experiencing a DFI greater than 5 years and 10 years in the ribociclib arm was 83.2% and 48.4%, respectively. In the placebo arm, 87.3% had a DFI of over 5 years and 44.6% of patients had a DFI greater than 10 years.

Study authors reported that a similar proportion of patients in the investigative and control arms had discontinued treatment, at 89.8% and 93.7%, respectively. Moreover, 86.2% and 90.6% of patients, respectively, received subsequent antineoplastic therapy.

In the ribociclib and placebo arms, patients who discontinued study treatment went on to receive chemotherapy alone (14.6% vs 16.8%), chemotherapy plus hormonal therapy/other (10.5% vs 9.4%), hormonal therapy only (34.0% vs 31.6%), hormonal therapy plus other (24.7% vs 30.9%), targeted therapy alone (1.6% vs 0.8%), targeted therapy plus other (0.4% vs 0%), immunotherapy alone (0.4% vs 0.4%), and other (0% vs 0.8%).

Of those who received subsequent treatment with CDK4/6 inhibitors, 16.2% of those in the investigative arm and 34.4% of those in the placebo arm received palbociclib (Ibrance); 5.3% and 2.0% of patients, respectively, received ribociclib; and 2.4% and 3.9% of patients, respectively, received abemaciclib (Verzenio).

Both CFS, and TTC were longer with the addition of ribociclib to letrozole vs letrozole alone in this patient population. The median TTC in the ribociclib arm was 54.1 months vs 40.9 months in the placebo arm (HR, 0.74; 95% CI, 0.59-0.93; P = .004). Median CFS was 42.5 months with ribociclib/letrozole vs 36.1 months with letrozole alone (HR, 0.75; 95% CI, 0.61-0.92; P = .002). These findings were comparable to the TTC and CFS data reported in the intention-to-treat population of MONALEESA-2, according to the study authors.

In terms of safety, the incidence of adverse effects (AEs) in this subgroup proved to be consistent with AEs previously seen in the study. No new safety signals were observed.

The most common grade 3 or higher AEs occurring in this subgroup included neutropenia (ribociclib, 53.5%; placebo, 0.7%), neutrophil count decrease (19.3%, 0.4%), hypertension (16%, 17.2%), white blood cell count decrease (13.5%, 0%), anemia (4.4%, 2.2%), alanine aminotransferase increase (11.6%, 6.7%), aspartate aminotransferase increase (6.5%, 0.7%),vomiting (4.4%; 1.1%), back pain (4%, 1.5%),fatigue (3.3%; 1.1%), nausea (2.9%; 1.1%), diarrhea (2.5%; 1.1%), arthralgia (1.5%, 1.9%), decreased appetite (1.5%, 0.4%), rash, (1.1%, 0.4%), constipation (1.1%, 0%) , headache (0.7%, 0.7%), hot flush (0.4%, 0%), and pain in extremities (0%, 0.4%).

Disclosures: Dr O'Shaughnessy reports having financial and personal interests with, and serving on an advisory board for AbbVie, Agendia, Amgen, Aptitude, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunome, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma, Prime, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre, Samsung, and Sanofi.

References

1. O’Shaughnessy J, Beck T, Chia S, et al. Efficacy and safety of first-line (1L) ribociclib (RIB) + letrozole (LET) in patients (pts) with de novo metastatic disease and late recurrence from (neo)adjuvant therapy (tx) in MONALEESA (ML)-2. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 196P.
2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663