Benefits of 1L ribociclib extend across MONALEESA studies
22 Jul 2023
byDr. Erika Hamilton
First-line (1L) treatment with the CDK4/6 inhibitor ribociclib plus endocrine therapy (RIB + ET) confers consistent benefits in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer in the pooled analysis of the MONALEESA-2, -3, and -7 studies presented at the San Antonio Breast Cancer Symposium (SABCS) 2022.
Overall, the duration of both 1L and second-line (2L) anticancer therapies was longer for patients treated with RIB vs placebo. Importantly, 2L chemotherapy was used less frequently in those treated with RIB vs placebo. [Hamilton E, et al, SABCS 2022, abstract P4-01-42]
“Both findings confirm that upfront treatment with RIB does not make the tumour more aggressive nor worsen outcomes in patients with HR+/HER2– advanced breast cancer,” said study author Dr Erika Hamilton, director of Breast Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology in Nashville, Tennessee, US. “The trend toward improved outcomes of 2L therapies after RIB suggests a post-treatment effect that merits further exploration.”
What is known for ribociclib
Ribociclib is indicated for the treatment of adults with HR+/HER2– advanced or metastatic breast cancer in combination with 1) an aromatase inhibitor as an initial ET in pre/perimenopausal or postmenopausal women or in men; or 2) fulvestrant as initial ET or following disease progression on ET in postmenopausal women or in men. [https://www.hsa.gov.sg/announcements/new-drug-indication-approvals/new-drug-indication-approval---october-2022]
The pivotal phase III MONALEESA-2, -3, and -7 trials showed consistent progression-free survival (PFS) and overall survival (OS) benefits with RIB + ET over ET alone in patients with HR+/HER2– advanced breast cancer regardless of menopausal status or ET partner. [N Engl J Med 2016;375:1738-1748; J Clin Oncol 2018;36:2465-2472; Lancet Oncol 2018;19:904-915; N Engl J Med 2020;382:514-524; N Engl J Med 2019;381:307-316; N Engl J Med 2022;386:942-950]
Additionally, benefits were seen for RIB + ET beyond study treatment, with improvements over placebo + ET in PFS on next-line treatment and delays in time to subsequent chemo. [N Eng J Med 2022; 386:942-950; SABCS 2020, abstract PD2-04; ASCO 2021, abstract 1001]
Treatment selection following disease progression
CDK4/6 inhibitor + ET remains the standard of care for HR+/HER2– metastatic breast cancer in the first-line setting. However, treatment selection for patients experiencing progression while on CDK4/6 inhibitor + ET remains challenging.
“There is no preferred next-line treatment post progression on a CDK4/6 inhibitor (except alpelisib for PIK3CA mutations),” said Hamilton. “Guidelines suggest multiple lines of ET-based regimens before switching to chemo, except in cases of visceral crisis or endocrine resistance.”
Continuing ET allows clinicians to delay chemo and maintain patients’ quality of life by minimizing treatment toxicities.
Pooled analysis of MONALEESA
Hamilton and her team assessed the relative outcomes of different subsequent treatment strategies after 1L RIB + ET or placebo + ET among patients with HR+/HER2– metastatic breast cancer. Data were pooled from patients receiving 1L therapy in MONALEESA-2, -3, and -7. Four groups of 2L therapies were assessed – ET only, CT (+/- any other therapy), targeted therapy (CDK4/6i, mTORi, PI3Ki, AKTi, etc, +/- ET), or other anticancer therapy not included in the first three groups. [Hamilton E, et al, SABCS 2022, abstract P4-01-42]
Median duration of 1L and 2L treatments, as well as median OS, were analysed using Kaplan-Meier methods. Weighted Cox regressions were performed using inverse probability treatment weighting to check for baseline characteristics.
With a median follow-up time of 74 months, 461 patients treated with RIB (81 percent) and 440 treated with placebo (86 percent) discontinued study treatment and received a 2L treatment. Common 2L therapies differed between arms.
“In the RIB arms, ET only was the most common 2L therapy [40 percent], followed by chemo [29 percent], combined with targeted therapy [28 percent], and other therapy [4 percent],” said Hamilton. “By comparison, chemo was the most common 2L therapy in the placebo arms [34 percent], followed by ET only or combined with targeted therapy [31 percent each]. Five percent received other therapy.”
In 14 percent and 20 percent of patients in the RIB and placebo arms, the 2L therapy was a CDK4/6 inhibitor. Of these, 31 percent and 12 percent were RIB.
Regardless of the type of 2L therapy, duration of both 1L and 2L therapies was generally longer for patients treated with RIB vs placebo (Figure). In both arms of the study, patients who received 2L chemo had the shortest study treatment duration. By comparison, those who went on to receive 2L targeted therapy combination, regardless of the treatment arm, had the longest study treatment duration.
Survival patterns after 1L RIB + ET
Among patients on 1L RIB plus ET, subsequent use of CDK4/6 inhibitor was associated with the longest median OS at 84 months, followed by ET monotherapy, and non-CDK4/6 inhibitor targeted therapy. Interestingly, 2L chemo was associated with the shortest mOS at 37.4 months (Table).
