Ribociclib plus endocrine therapy for hormone receptor–positive, HER2-negative advanced breast cancer following progression on a CDK4/6 inhibitor bests matched placebo.
Results of the randomized phase 2 MAINTAIN trial (NCT02632045) demonstrated improved progression-free survival (PFS) with endocrine therapy plus ribociclib (Kisqali) vs placebo for patients with hormone receptor–positive, HER2-negative unresectable or metastatic breast cancer who experienced progressive disease following prior CDK4/6 inhibitor therapy, according to results presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.
The median progression-free survival (PFS) for patients on ribociclib plus endocrine therapy was 5.29 months (95% CI, 3.02-8.12) compared with 2.76 months (95% CI, 2.66-3.25) with placebo and endocrine therapy, representing a 43% reduction in the risk of progression or death (HR, 0.57; 95% CI, 0.39-0.95; P = .006). At 12 months, the PFS rates were 24.6% (95% CI, 12.5%-36.7%) with ribociclib and 7.4% (95% CI, 0.4%-14.3%) without.
The clinical benefit rate (CBR) was also significantly improved in the ribociclib arm of the MAINTAIN trial compared with the placebo arm at 43% vs 25%, respectively (P = .06).
Prior to the trial, the benefit of CDK4/6 inhibition with endocrine therapy was established across large phase 3 trials, but only observational data suggested the benefit for switching endocrine therapy after progression on the primary CDK4/6 inhibitor, as the benefit of inhibition can end once treatment is concluded.
“This is the first randomized trial to show the benefit of ribociclib and switching endocrine therapy after progression on a CDK4/6 inhibitor,” said Kevin Kalinsky, MD, MS, an associate professor in the Department of Hematology and Medical Oncology, the Louisa and Rand Glenn Family Chair in Breast Cancer Research, director of Glenn Family Breast Center, and director of breast medical oncology at the Winship Cancer Institute of Emory University, in his presentation of these data at the ASCO meeting.
MAINTAIN randomized 119 evaluable patients to receive either 600 mg of ribociclib for 3 weeks on and 1 week off plus switch endocrine therapy (n = 60) or placebo and switch endocrine therapy (n = 59). Eligible patients were adult men or women with metastatic breast cancer and hormone receptor positivity of at least 1% and HER2 negativity.
All patients had progressed on prior endocrine therapy and any CDK4/6 inhibitor having received up to 1 prior line of chemotherapy for metastatic disease. Patients were expected to be postmenopausal, although a gonadotropin-releasing hormone agonist was allowed if the patient was premenopausal, and patients with stable brain metastases were allowed in the trial.
The primary end point was locally assessed PFS by RECIST criteria and secondary end points included overall response rate (ORR), CBR, safety, and tumor and blood markers. Statistical analyses required that about 120 patients be randomized to achieve 80% power to detect a difference of 3 months in PFS with a one-sided log-rank at 2.5%.
The median age of patients was 55 years in the ribociclib arm and 59 in the placebo arm; all but 1 patient in both arms was female. Across treatment arms, most patients were White (74%) but 11% were Black and 6% were Asian, most had an ECOG performance status of 0 (66%) vs 1 (34%), and most had visceral metastasis (60%). Additionally, 45% had de novo metastasis at diagnosis, 18% had bone-only disease, 18% had received 2 or more prior endocrine therapies for metastatic disease, and 9% had received chemotherapy.
Most patients had received palbociclib (Ibrance) as their first CDK4/6 inhibitor (87% in ribociclib arm vs 86% in placebo arm), followed by ribociclib (10% vs 14%, respectively). Two patients (3%) in the ribociclib arm had previously received abemaciclib (Verzenio). The median duration of treatment with the prior CDK4/6 inhibitor was 15.5 months (interquartile range [IQR], 12-21) in the ribociclib arm and 17 months (IQR, 11-23.5) in the placebo arm. Prior CDK4/6 inhibition was given in the metastatic setting for all patients and required intervening therapy after progression in 7 patients (6%).
As of the data cutoff date of January 4, 2022, patients were followed for a median of 18.2 months and 8 patients remained on treatment in the ribociclib arm and 1 in the placebo arm.
Among 70 patients evaluable for ORR, the response rate was 20% with ribociclib compared with 11% with placebo (P = .51); moreover, complete responses were observed in 2 patients (6%) in the ribociclib arm.
The median duration of response was 18.8 months (IQR, 11.4-50.2) in those treated with ribociclib and endocrine therapy compared with 14.8 months (IQR, 6.7-21.3) for those treated with endocrine therapy alone. CBR, defined as patients who achieved complete response, partial response, or stable disease lasting at least 24 weeks, was also measured in 105 evaluable patients.
Dose interruptions were required in 60% of patients in the ribociclib arm compared with 34% in the placebo arm, with 53% and 20%, respectively, due to adverse events (AEs). Dose reductions occurred in 23% of patients in the CDK4/6 arm and in 8.5% of the placebo arm due to AEs in 23% of the treatment arm and 8.5% in the placebo arm.
Hematologic AEs were more common with ribociclib, and non-hematologic AE rates were similar between the 2 groups. Neutropenia was the most common hematologic event at any grade (72% with ribociclib vs 15% with placebo; febrile neutropenia in 3% vs 0%, respectively) followed by thrombocytopenia (25% vs 5%), and anemia (23% vs 22%). Fatigue was the most common non-hematologic event at any grade at 33% with ribociclib vs 32% with placebo, followed by aspartate aminotransferase increase (25% vs 29%, respectively), alanine aminotransferase increase (17% vs 20%), diarrhea (15% vs 10%), and vomiting (15% vs 5%).
The most common grade 3 AE was neutropenia, observed in 38% of the ribociclib, and the only grade 4 event was neutropenia observed in 1 patient in each arm. Treatment-related deaths were reported in 3 patients across the trial, 2 in the ribociclib arm and 1 in the placebo arm.
Across subgroup analyses, PFS favored the ribociclib arm over the placebo arm, especially for patients with a shorter prior CDK4/6 inhibition duration (HR, 0.36; 95% CI, 0.17-0.75) and those over age 65 (HR, 0.31; 95% CI, 0.12-0.80).
By endocrine therapy, patients who received exemestane (n = 20) had a greater benefit from ribociclib addition than those who received fulvestrant (n = 99). The median PFS with ribociclib in the exemestane subgroup was 5.36 months (95% CI, 3.02-14.50) compared with 3.06 months (95% CI, 1.84-5.95) with placebo (HR, 0.41; 95% CI, 0.14-1.24). In the fulvestrant subgroup, the median PFS was 5.29 months (95% CI, 2.96-8.12) with ribociclib and 2.76 months (95% CI, 2.66-3.25) without (HR, 0.60; 95% CI, 0.39-0.94).
At study entry, 42% of 78 evaluable patients with circulating tumor DNA had an ESR1 mutation. In these 33 patients, co-occurring alterations of TP53 mutation, PIK3CA mutation, CCND1 amplification, and FGFR1 amplification were reported in 30%, 21%, 24%, and 9%, respectively. In the remaining ESR1 wild-type patients, TP53 and PIK3CA mutations were each reported in 33% of patients, but CCND1 amplifications were in 2% and FGFR1 amplifications in 6%.
Patients with ESR1 wild-type showed a greater improvement from ribociclib than patients with an ESR1 mutation. In the ESR1 wild-type group, the median PFS was 8.32 months (95% CI, 5.65-16.63) with ribociclib vs 2.76 months (95% CI, 2.66-5.49) without. Median PFS with ribociclib in the ESR1-mutant group was 2.96 months (95% CI, 2.66-4.21) vs 3.02 months (95% CI, 2.53-5.62) with placebo. Fifty percent of patients in the ESR1-mutant group in the ribociclib arm had co-occurring CCND1 and/or FGFR1 amplifications.
Due to the small sample size of the ESR1-mutant subgroup, Kalinsky noted that these data were only hypothesis generating.
Kalinsky K, Accordino MK, Chiuzan C, et al. A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. J Clin Oncol. 2022;40(suppl 16):LBA1004. doi:10.1200/JCO.2022.40.16_suppl.LBA1004