Continuous Low-Dose Ribociclib Both Safe and Active in Advanced Breast Cancer

Sara Tolaney, MD, MPH

A continuous low-dose of ribociclib demonstrated both preliminary activity and an acceptable safety profile when compared with an intermittent dose of ribociclib when combined with fulvestrant in the treatment of postmenopausal patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. The results of this phase Ib study were presented at the 2016 San Antonio Breast Cancer Symposium.

Patients treated with continuous ribociclib showed a confirmed partial response (PR) of 13.3%, compared with 23.1% in the intermittent ribociclib arm. Moreover, patients receiving the continuous dose of ribociclib also experienced a lower rate of high-grade neutropenia.

“Giving ribociclib continuously is associated with less neutropenia compared to the higher dose on a 3 week-on/1 week-off schedule,” said lead investigator Sara Tolaney, MD, MPH, associate clinical research director of Breast Oncology at the Dana-Farber Cancer Institute in Boston. “We’re also seeing activity in both arms, which is reassuring that even when you lower the dose and give it continuously, you see PR in both arms. This is a heavily pretreated population; they could even have received prior fulvestrant, yet we’re still seeing prolonged stable disease (SD) and PRs, so that’s pretty exciting.”

The ongoing phase Ib study has 2 other arms investigating the triplet therapy. Preliminary results from only the doublet arm were presented. Ribociclib is a Cyclin dependent kinase (CDK)4/6 inhibitor; dysregulation of the CDK4/6-Cyclin D (CCND1)-retinoblastoma and PI3K/mTOR pathways are common in breast cancer, and have been implicated in endocrine therapy resistance. CDK4/6 and PI3K/mTOR inhibitors have been shown to act synergistically with endocrine therapy in preclinical and clinical studies of HR-positive breast cancer.

Patients in the doublet arm were treated with once-daily ribociclib at either 600 mg/day on a 3-weeks on/1-week off schedule (arm A) or 400 mg/day continuous (arm B) plus fulvestrant, 500 mg/day on day 1 and day 15 of cycle 1/day 1 of subsequent cycles.

Included in the study were postmenopausal women with HR-positive, HER2-negative metastatic or locally advanced breast cancer, whose disease progressed either during or within 12 months of prior adjuvant aromatase inhibitor (AI) therapy or during or within 1 month of AI therapy for metastatic disease. Patients were allowed to receive up to 2 prior lines of chemotherapy for advanced disease, and any number of lines of prior endocrine therapy. Patients with significant cardiac disease or impaired cardiac function were excluded.

Twenty-eight patients, 13 in arm A and 15 in arm B, comprised the doublet arm as of September 12, 2016. Their mean age was 59 years. Patients had received a median of 4 prior antineoplastic therapies. In the metastatic setting, 42.9% received prior chemotherapy (61.5% in arm A vs 26.7% in arm B), 92.9% received prior endocrine therapy, 38.6% received prior PI3K/mTOR inhibitor therapy (23.1% in arm A vs 33.3% in arm B). At the data cut-off, 78.6% of patients discontinued treatment (100% in arm A vs 60.0% in arm B). The most common reason for discontinuation was progressive disease (84.6%).

The most common adverse events (AEs) thought to be study drug-related were neutropenia (64.3%), fatigue (42.9%), and nausea (42.9%), and the most common grade 3/4 AEs thought to be study drug-related were neutropenia (46.4%) and a decrease in white blood cell count (10.7%). Grade 3/4 neutropenia occurred in 61.5% of the intermittent arm, compared with 33.3% of the continuous dosing arm, and the rates of grade 3/4 fatigue were 15.4% and 0%, respectively.

Out of the patients on the intermittent schedule (arm A), 23.1% had a confirmed PR, 69.2% had SD, and 7.7% with non-measureable disease had neither complete response nor progressive disease. The best overall responses in the 7 patients who had received prior fulvestrant were a confirmed PR in 2 patients and SD in 5 patients.

In the continuous ribociclib arm (arm B), 13.3% had a confirmed PR, 46.7% had SD, and 6.7% had progressive disease. The best overall responses in the 6 patients who had received prior fulvestrant were a confirmed PR in 1, SD in 3, non-measureable disease with neither complete response nor progressive disease in 1, and progressive disease in 1.

Next-generation sequencing analysis was performed on tumor samples form 16 patients (7 in arm A and 9 in arm B). Alterations in PI3K3CA were present in 11 patients; of these, 1 had a PR, 7 had SD, and 3 experienced non-measureable disease with neither complete response nor progressive disease. Two patients with alterations in both CCND1 and PIK3CA experienced a SD and non-measureable disease, with neither complete response nor progressive disease.

“To see responses in patients who’ve had prior fulvestrant and have had up to 2 lines of chemotherapy is good,” said Tolaney. “Ribociclib seems active regardless of the presence of PI3K mutation. There is maybe a hint that those who have Cyclin-D amplification may have prolonged durability, at least SD, but the numbers here are very small, and you can’t conclude much from this. It’s more exploratory.”

Tolaney SM, Forero-Torres A, Boni V, et al. Ribociclib + fulvestrant in postmenopausal women with HR+, HER2- advanced breast cancer (ABC). Presented at 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P4 22-12.